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What are 'gap junctions' (electrical synapses) for?

What are 'gap junctions' (electrical synapses) for?

I was reading this and I found the following sentences:

Apart from chemical synapses neurons can also be coupled by electrical synapses, so-called gap junctions. Specialized membrane proteins make a direct electrical connection between the two neurons. Not very much is known about the functional aspects of gap junctions, but they are thought to be involved in the synchronization of neurons.

Do we really know very little about the functional aspects of gap junctions? And how are they involved the 'synchronization' of neurons?


Gap junctions can couple cells directly electrically. Cell types electrically coupled via gap junctions include neurons, the pancreatic islets of Langerhans (Andreu et al, 1997) and cardiac cells (Fig. 1.). In contrast to chemical synapses, information transfer via electrical "synapses" (gap junctions) is nearly instantaneous. In chemical information flow, the synapse is the rate limiting step, because it depends on the passive diffusion of neurotransmitters across the synaptic cleft.


Fig. 1. The pacemaker potential in cardiac muscle cells spreads rapidly across the surface of the heart to generate synchronous muscle contraction. Source: Austin Community College.

Moreover, in a structure such as a brain nucleus many cells can be coupled. In other words, if all cells in a tissue contain gap junctions, all these cells are directly electrically coupled, not just those cells directly touching each other. In a way, all cells in such a tissue are in open connection with each other. This means that when one cell fires, it can theoretically activate all the connected cells to fire an action potential in near-synchrony.

Hence, gap junctions allow for synchronous activation of inter-connected neurons, both in the spatial and temporal domain.

While this can be the preferred mode of operation of firing in some neuronal structures such as the olivary nucleus (Leznik & Llinás, 2005), it can theoretically lead to trouble in case pathological synchronization is established, leading to epileptic activity (Dudek, 2002).

Whether we know little, or much of gap junctions is subjective. However, it is certainly true that way more research is available on chemical neurotransmission than on electrical transmission. Likewise, many more medications target chemical transmission than electrical neurotransmission.

References
- Andreu et al, J Physiol (1997), 498(3): 753-61
- Dudek, Epilepsy Curr (2002); 2(4): 133-6
- Leznik & Llinás, J Neurophysiol (2005); 94(4): 2447-56


Neural connectivity

Numerous studies have shown that neurons are not connected in an anarchic way to each other, but that the relationships between different nerve centers they follow guidelines that transcend a particular animal species, being characteristic of the animal group.

This connectivity between different nerve centers arises during embryonic development and is perfected as it grows and develops. The basic wiring in different vertebrate animals shows a general resemblance, a reflection of gene expression patterns inherited from common ancestors.

During the differentiation of a neuron, its axon develops guided by the chemical characteristics of the structures which were in its stage and these serve as a reference for knowing how to position and position itself within the neural network.

Neural connectivity studies have also shown that there is generally a predictable correspondence between the position of neurons at the center of origin and that of their axons at the center of destination, and accurate topographic maps of the connection can be made between the two. areas.


Electrical Coupling in Caenorhabditis elegans Mechanosensory Circuits

I. Rabinowitch , W.R. Schafer , in Network Functions and Plasticity , 2017

Abstract

Electrical synapses formed by gap junctions are widespread in the human brain as well as in simpler nervous systems. The nematode Caenorhabditis elegans, with its completely mapped connectome of 302 neurons and approximately 4000 electrical synapses, is therefore well suited to investigate the functional importance of electrical coupling in neuronal microcircuits. We have found that hub-and-spoke gap junction circuit in C. elegans mediates the integration of mechanosensory information to control nose touch avoidance behavior. A combination of lateral facilitation between active inputs and inhibitory shunting to inactive inputs implements an analog coincidence detector, a property that might be shared with other hub-and-spoke circuits. We also describe transgenic methods for the synthetic insertion of ectopic gap junctions, which may have broad experimental applications.


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Gap junctions

In vertebrates and invertebrates, signaling among neurons is most commonly mediated by chemical synapses. At these synapses neurotransmitter released by presynaptic neurons is detected by receptors on the postsynaptic neurons, leading to an influx of ions through the receptors themselves or through channels activated by intracellular signaling downstream of the receptors. But neurons can communicate with each other in a more direct way, by passing signals composed of small molecules and ions through pores called gap junctions. Gap junctions that transmit electrical signals are called electrical synapses. Unlike most chemical synapses, electrical synapses interact through axon-to-axon or dendrite-to-dendrite contacts. Found throughout the nervous system, they are probably best known for linking the relatively few inhibitory, GABAergic, neurons into large, effective networks within vertebrate brains. They are particularly important early in development before the formation of most chemical synapses, but recent work shows gap junctions play important roles in the adult nervous system, too. Gap junctions are sometimes thought to be mere passageways between cells. But, as recent work shows, their properties can be complex and surprising. Gap junctions help generate, propagate, and regulate neural oscillations, can filter electrical signals, and can be modulated in a variety of ways. Here we discuss recent work highlighting the diversity and importance of gap junctions throughout the nervous system.


  • Stereotypy
  • stereotypical
  • nodes of Ranvier
  • dendrite
  • olfactory
  • myelination
  • autism
  • plastic
  • glia
  • myelin
  • blood-brain barrier
  • glial cell
  • axon
  • stereotyped
  • apoptosis
  • nodes of ranvier
  • stimuli
  • neurotransmitter
  • neuron

Mechanics of the Action Potential

  • The synapse is the junction where neurons trade information.
  • The stages of an electrical reaction at a synapse are as follows:
  • Chemical synapses are much more complex than electrical synapses, which makes them slower, but also allows them to generate different results.
  • Electrical synapses are faster than chemical synapses because the receptors do not need to recognize chemical messengers.
  • Long-term changes can be seen in electrical synapses.

Neuroplasticity

  • Learning takes place when there is either a change in the internal structure of neurons or a heightened number of synapses between neurons.
  • At birth, there are approximately 2,500 synapses in the cerebral cortex of a human baby.
  • By three years old, the cerebral cortex has about 15,000 synapses.
  • Apoptosis occurs during early childhood and adolescence, after which there is a decrease in the number of synapses.
  • The selection of the pruned neurons follows the "use it or lose it" principle, meaning that synapses that are frequently used have strong connections, while the rarely used synapses are eliminated.

Neurotransmitters

  • Neurotransmitters are chemicals that transmit signals from a neuron across a synapse to a target cell.
  • Neurotransmitters are chemicals that transmit signals from a neuron to a target cell across a synapse.
  • There are several systems of neurotransmitters found at various synapses in the nervous system.
  • Amino acid neurotransmitters are eliminated from the synapse by reuptake.
  • Neuropeptides are often released at synapses in combination with another neurotransmitter.

Cognitive Development in Childhood

  • Once nerve cells in the brain are in place, they form synapses.
  • These synapses release neurotransmitters, which are chemical signals that help the brain communicate.
  • Synapses evolve rapidly, and in doing so, some synapses will die off to make room for new or more important ones.
  • This process improves message transfer between synapses and assists in brain development.
  • Synapses, or the spaces between nerve cells, develop rapidly during childhood.

Habituation, Sensitization, and Potentiation

  • One way that the nervous system changes is through potentiation, or the strengthening of the nerve synapses (the gaps between neurons).
  • In neural communication, a neurotransmitter is released from the axon of one neuron, crosses a synapse, and is then picked up by the dendrites of an adjacent neuron.
  • During habituation, fewer neurotransmitters are released at the synapse.
  • This image shows the way two neurons communicate by the release of the neurotransmitter from the axon, across the synapse, and into the dendrite of another neuron.
  • Communication between neurons occurs when the neurotransmitter is released from the axon on one neuron, travels across the synapse, and is taken in by the dendrite on an adjacent neuron.

Introducing the Neuron

  • The synapse is the chemical junction between the axon terminals of one neuron and the dendrites of the next.
  • One neuron's axon will connect chemically to another neuron's dendrite at the synapse between them.
  • Electrically charged chemicals flow from the first neuron's axon to the second neuron's dendrite, and that signal will then flow from the second neuron's dendrite, down its axon, across a synapse, into a third neuron's dendrites, and so on.
  • Dendrites, cell bodies, axons, and synapses are the basic parts of a neuron, but other important structures and materials surround neurons to make them more efficient.
  • The interface between a motor neuron and muscle fiber is a specialized synapse called the neuromuscular junction.

Basic Principles of Classical Conditioning

  • However, since these pathways are being activated at the same time as the other neural pathways, there are weak synapse reactions that occur between the auditory stimuli and the behavioral response.
  • Over time, these synapses are strengthened so that it only takes the sound of a buzzer to activate the pathway leading to salivation.

Other Steps

  • An electrical impulse crosses a synapse between neurons in the brain, releasing a neurotransmitter.
  • Dendrites, which are extensions of neurons, receive the impulse and allow the synapse to increase in strength this is known as long-term potentiation.

Neural Networks

  • The basic kinds of connections between neurons are chemical synapses and electrical gap junctions, through which either chemical or electrical impulses are communicated between neurons.
  • The method through which neurons interact with neighboring neurons usually consists of several axon terminals connecting through synapses to the dendrites on other neurons.
  • Neurons interact with other neurons by sending a signal, or impulse, along their axon and across a synapse to the dendrites of a neighboring neuron.

Basic Principles of Classical Conditioning: Pavlov

  • However, because these pathways are being activated at the same time as the other neural pathways, there are weak synapse reactions that occur between the auditory stimulus and the behavioral response.
  • Over time, these synapses are strengthened so that it only takes the sound of a buzzer (or a bell) to activate the pathway leading to salivation.
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Contents

The function of neurons depends upon cellular polarization. The distinctive structure of nerve cells allows action potentials to travel directionally (from dendrites to axons), and for these signals to then be received and carried on by post-synaptic neurons or received by effector cells. Nerve cells have long been used as models for cellular polarization, and of particular interest are the mechanisms underlying the polarized localization of synaptic molecules. PIP2 signalling regulated by IMPase plays an integral role in synaptic polarity.

Phosphoinositides (PIP, PIP2, and PIP3) are molecules that have been shown to affect neuronal polarity. Ε] They are synthesized by combinational phosphorylation of phosphatidylinositol (PI), a phospholipid cell membrane component. PI is derived from myo-inositol, which is obtained via three pathways: uptake from the extracellular environment, synthesis from glucose, and the recycling of phosphoinositides. Both the synthesis of myo-inositol from glucose and the recycling of phosphoinositides require myo-inositol monophosphatase – IMPase – an enzyme that produces inositol by dephosphorylating inositol phosphate. Ζ] IMPase has been studied in vivo at some length due to its relevance in the study of bipolar disorder resulting from its sensitivity to lithium. Η] In 2006, a gene (ttx-7) was identified in Caenorhabditis elegans that encodes IMPase. Organisms with mutant ttx-7 genes demonstrated behavioral and localization defects, which were rescued by expression of IMPase and application of inositol. Wild type organisms treated with lithium displayed similar defects to those exhibited by the ttx-7 mutants. This led to the conclusion that IMPase is required for the correct localization of synaptic protein components. ⎖]

The egl-8 gene encodes a homolog of phospholipase Cβ (PLCβ), an enzyme that cleaves PIP2. When ttx-7 mutants also had a mutant egl-8 gene, the defects caused by the faulty ttx-7 gene were largely reversed this suggests that an accumulation of PIP2 corrected the adverse effects of the mutant ttx-7 gene. Furthermore, a mutation in the unc-26 gene (encoding a protein that dephosphorylates PIP2) suppressed the synaptic defects in the ttx-7 mutants. The egl-8 mutants were resistant to lithium treatment. This is genetic evidence that disruption of IMPase alters the levels of PIP2 in neurons these results suggest that PIP2 signaling establishes polarized localization of synaptic components in living neurons. Ζ]


Plasticity of Retinal Gap Junctions: Roles in Synaptic Physiology and Disease

Electrical synaptic transmission via gap junctions underlies direct and rapid neuronal communication in the central nervous system. The diversity of functional roles played by electrical synapses is perhaps best exemplified in the vertebrate retina, in which gap junctions are expressed by each of the five major neuronal types. These junctions are highly plastic they are dynamically regulated by ambient illumination and circadian rhythms acting through light-activated neuromodulators. The networks formed by electrically coupled neurons provide plastic, reconfigurable circuits positioned to play key and diverse roles in the transmission and processing of visual information at every retinal level. Recent work indicates gap junctions also play a role in the progressive cell death and aberrant activity seen in various pathological conditions of the retina. Gap junctions thus form potential targets for novel neuroprotective therapies in the treatment of neurodegenerative retinal diseases such as glaucoma and ischemic retinopathies.

Keywords: connexins electrical synapses gap junctions neurodegeneration retina.


Rectifying electrical synapses in pattern-generating circuits

Rectifying electrical synapses are more interesting than they might seem at first. Our recent study finds that they have the potential to allow a circuit to control how robust the circuit output is to modulation of synaptic strength.

Gap junctions allow neurons to communicate quickly by serving as a direct conduit of electrical signals. Non-rectifying gap junctions probably come to mind first for most neuroscientists when they think about electrical synapses, since they are the idealized textbook variety. The electrical current that passes through the non-rectifying type of gap junction is simply a function of the voltage difference between the coupled neurons. However, this is only the case when the two hemi-channels that form a gap junction pore have the same voltage-dependencies.

Schematic shows that neurons can express diverse gap junction subunits (top left). Rectifying gap junction conductance is a function voltage difference between two neurons (top right). Bottom panel illustrates how coupled neuron output depends on the polarity of the rectifying electrical synapse and the intrinsic properties of the coupled neurons.

We know from past electrophysiology studies that a single neuron can express a diverse set of gap junction hemi-channels, enabling it to form similarly diverse gap junction channels with another neuron. This could result in rectifying electrical synapses in which current flows asymmetrically between neurons so that current flow can either be permitted or restricted depending on whether the current is positive or negative. What we didn’t know were the consequences of electrical synapse rectification for a pattern-generating circuit of competing oscillators. Our recently published study in J. Neuroscience addressed this question and led us to conclude that rectifying electrical synapses can change how a neuronal circuit responds to modulation of its synapses – including its chemical synapses. Although we used a computational model for our study, our results indicate that rectifying electrical synapses in biological networks can be an important component in neuronal circuits that produce rhythmic patterns, such as those found in motor systems.

Gabrielle Gutierrez obtained her PhD in Neuroscience from Brandeis earlier this year, and is currently doing a postdoc with Sophie Deneuve at the Ecole Normale Superieure in Paris

Gutierrez GJ, Marder E. Rectifying electrical synapses can affect the influence of synaptic modulation on output pattern robustness. J Neurosci. 201333(32):13238-48.


SURPRISING AND PUZZLING RESULTS FROM CONNEXIN MUTATIONS

Other functions that emerge from connexin deletions may result from the loss of a complex interplay of multiple connexin-family members in an incompletely defined network, producing unexpected and unexplained outcomes. Some of these examples are explored here in more detail.

Gap Junctions in the Vascular System

Arterioles are composed of a longitudinal layer of endothelial cells facing the blood, which is separated by a basal lamina from a layer of circular smooth muscle cells that control lumen diameter. There is a surprising complexity of connexin expression in the arteriolar layers. Smooth muscle cells express mainly Cx43 (Gabriels and Paul 1998) and endothelial cells mainly Cx40 (Little et al. 1995 van Kempen and Jongsma 1999), although both cell types express both connexins. Cx32 expression has been reported in endothelial cells (Okamoto et al. 2009). Smooth muscle cells uniquely express Cx45 (Kruger et al. 2000), whereas only the endothelium contains Cx37 (Gabriels and Paul 1998 van Kempen and Jongsma 1999). In addition, there can be significant regional variations in the relative abundance of these connexins in the vessel wall. As an example, endothelial Cx43 is dramatically up-regulated at the expense of the other connexins in areas that experience shear stresses such as vessel branch points (Gabriels and Paul 1998). Not only are gap junctions formed within arteriolar layers, but junctions are also formed between smooth muscle and endothelial cells. The connexin content of the myoendothelial junctions is not yet clear, although in vitro studies suggest that the endothelial side contains largely if not exclusively Cx40 (Isakson and Duling 2005).

Gap junctions have been strongly implicated in the conducted spread of vasodilation. Local endothelial stimulation initiates a rapidly propagated, bidirectional wave of relaxation along the vessel axis (Welsh and Segal 1998 Figueroa et al. 2003 de Wit et al. 2006). An intact endothelium is required for conducted vasodilation, which does not decay with distance and so must contain a self-regenerative component. The propagation of vasomotor activity is significantly depressed in Cx40 KO but not Cx37 KO animals (Figueroa et al. 2003 de Wit et al. 2000). While it was initially surprising that the loss of Cx37, which is co-expressed in endothelial cells, had no effect on propagation, this could be explained by the fact that loss of Cx40 causes a dramatic (㸠-fold) reduction in the levels of endothelial Cx37, while loss of Cx37 results in only a mild (𢏏ourfold) reduction in the levels of Cx40 (Simon and McWhorter 2003).

A simple model for the role of gap junctions in propagation is that endothelial stimulation results in a change in membrane potential that is passively conducted along the endothelial layer through gap junctions, critically those containing Cx40. However, this model does not explain self-propagation. Even more problematic, knockin of Cx45 into the Cx40 locus does not rescue the Cx40 KO phenotype, suggesting that ionic spread of membrane potential changes through endothelial𠄾ndothelial gap junctions is not a critical factor (Wolfle et al. 2007). On the other hand, studies using connexin-mimetic peptides to selectively inhibit junctional communication in rabbit iliac arteries suggest that although Cx40 is required for endothelium-dependent smooth muscle hyperpolarization, Cx43 is required for spread of that hyperpolarization within the smooth muscle layer (Chaytor et al. 2005). Taken together, these observations suggest another model in which propagation requires both myoendothelial gap junctions as well as gap junctions joining smooth muscle cells. In the first phase, endothelial stimulation leads to release of an endothelium-derived hyperpolarizing factor (EDHF), causing hyperpolarization of immediately adjacent smooth muscle. It has been suggested that EDHF signaling requires myoendothelial junctions (Griffith 2007), which are permeable to inositol trisphosphate and Ca 2+ (Isakson et al. 2007). A second phase might involve electrotonic spread of hyperpolarization within the smooth muscle layer through gap junctions composed of Cx43. The extent of this spread would be modest as electrical coupling in this layer is relatively weak. In the third phase, smooth muscle must restimulate endothelial cells distal to the site of initial stimulus, regenerating additional rounds of EDHF release. Relaxation of smooth muscle accompanies release of a second factor, endothelium-derived relaxation factor (likely nitric oxide), which can move from endothelium to smooth muscle in the absence of gap junctions. This model is consistent with the loss of conducted vasodilation in the Cx40 KO, but not Cx37 KO, and predicts a Cx40 KO phenocopy in a smooth muscle-specific Cx43 KO, which has not yet been evaluated.

In addition to vasomotor responses, connexin knockouts can dramatically impact systemic blood pressure. Conditional disruption of Cx43 in vascular endothelial cells results in hypotension and bradycardia (Liao et al. 2001), accompanied by elevated plasma levels of nitric oxide because of increased activity of endothelial nitric oxide synthase. These phenotypes are currently without explanation and are not seen in another model of vascular deletion of Cx43 (Theis et al. 2001). In contrast to the hypotension accompanying vascular loss of Cx43, constitutive deletion of Cx40 results in hypertension (de Wit et al. 2006). In this case, disregulation of angiotensin levels may be responsible. In these animals, renin-producing cells are anatomically displaced during development (Kurtz et al. 2007) and are also less responsive to feedback inhibition by plasma angiotensin, leading to increased plasma levels of renin (Wagner et al. 2007). Why the loss of Cx40 results in this cellular localization defect is not known. Interestingly, although knockin of Cx45 into the Cx40 locus is unable to rescue propagation of the vasomotor activity (Wolfle et al. 2007), it abrogates the hyperreninemia, partially attenuating the systemic hypertension and restoring angiotensin-suppression of renin release (Schweda et al. 2008). Parenthetically, Cx45 deletion from smooth muscle in the juxtaglomerular apparatus later in development also results in increased renin secretion and significant blood pressure elevation (Hanner et al. 2008 Yao et al. 2008).

The double knockout (dKO) of Cx37 and Cx40 displays an additional phenotype not seen in either individual knockout. dKO animals die perinatally with dramatic vascular abnormalities. By E18.5, numerous hemorrhages are visible through the skin and internally in the testes, lungs, and intestines. Vasculogenesis is aberrant in the testis and in the connective tissues of the small bowel, but seemingly unaffected in other organs (Simon and McWhorter 2002 Simon and McWhorter 2003). It is not known if these new pathologies result from a combination of the individual regulation and selectivities of the individual connexins, or if this is because of unique properties exhibited by heteromeric or heterotypic intercellular channels.

Gap Junctions in the Ocular Lens

During development, the optic vesicle induces the overlying ectoderm to invaginate and pinch off a hollow sphere of cells, the lens vesicle. The posterior cells of the vesicle then elongate anteriorly as lens fibers, which contact the anterior cells occluding the vesicle lumen. The lens thus becomes a solid cyst of cells, with an anterior epithelium and posterior fibers. The organ eventually loses an enveloping basket of blood vessels, becoming totally avascular and therefore dependent on the aqueous humor for all metabolic needs. The lens continues to grow in volume throughout the life of the organism by appositional growth, differentiating new lens fibers from a stem cell population at the equatorial surface. The older fibers do not turn over, remaining in the lens interior. To achieve a high refractive index and transparency, the differentiating fibers synthesize high concentrations of soluble proteins, the crystallins, and then undergo a limited apoptosis, destroying their nuclei and all light-scattering organelles. Thus, the lens fibers are metabolically dependent on the anterior epithelial cells that retain their organelles. The lens fibers are joined to each other and to the epithelial cells by large numbers of gap junctions (Goodenough 1992). The asymmetric location of the Na + K + ATPase in the epithelium results in a translenticular potential and a DC current flow (Candia et al. 1970), modeled as the circulatory system of the lens (Rae 1979 Mathias 1985 Mathias and Rae 1989). As the high concentration of the crystallins requires a tight control of ionic balance to remain in solution, the ionic syncytium created by the gap junctions is essential for lens transparency.

Cx43, 46, and 50 are expressed in the lens. Cx43 and 50 are found abundantly in the lens epithelium (Beyer et al. 1987 Jiang et al. 1995 Martinez-Wittinghan et al. 2003). Cx46 and 50 are found joining the lens fibers where they colocalize to the same junctional plaques (Paul et al. 1991) and have been shown to co-oligomerize into the same connexons and intercellular channels (Konig and Zampighi 1995 Jiang and Goodenough 1996). Indeed, immunofluorescence studies have shown colocalization of Cx46 and 50 in all junctional plaques joining the fibers. Given this anatomical overlap, it is surprising that targeted deletion of Cx46 and 50 result in distinctly different phenotypes (Gong et al. 1997 White et al. 1998). First, both cause cataracts but with differences in timing of onset and in morphology. Second, deletion of Cx50, but not Cx46, results in a slower postnatal growth rate with concomitant decrease in lens size and microphthalmia (White et al. 1998). Interestingly, the normal growth rate is uniquely dependent on Cx50 because replacing the coding region of Cx50 with that of Cx46 (Cx50 46/46 ) does not fully rescue the lens mitotic rate (White 2002 Sellitto et al. 2004). The identity of the Cx50-dependent signal controlling mitosis is not known (White et al. 2007). The Cx46/Cx50 double knockout shows a phenotype more severe but predictable as the sum of the two individual connexin deletions (Xia et al. 2006).

Cx50 46/46 animals are completely free of cataracts (White 2002), suggesting that this pathology could be prevented by simply restoring adequate numbers of junctional channels. Thus, it is surprising that mice heterozygous for Cx46 and Cx50 at the Cx50 locus (Cx50 +/46 ) develop a cataract (Martinez-Wittinghan et al. 2003). Furthermore, this cataract is morphologically different from those in either Cx46KO or Cx50KO lenses. Although the latter two are primarily nuclear, the Cx50 +/46 cataract is largely subepithelial. Additional crosses show that the Cx50 +/46 cataract is insensitive to dosage of Cx46 at the Cx46 locus, proving that this unexpected phenotype is the result of changes in connexin stoichiometry in the epithelium, where Cx46 is not normally detected. Importantly, the phenotype only occurs when Cx50 and Cx46 are coexpressed in the epithelium, because no cataract is observed in the homozygous (Cx50 46/46 ) knockin (White 2002). In addition to the cataract, Cx50 +/46 lenses display impaired dye transfer both within the epithelial plane and between epithelium and underlying fibers (Martinez-Wittinghan et al. 2003). Why mixing of Cx46 and Cx50 in the epithelium should depress dye transfer and cause a novel cataract is completely without explanation because those connexins functionally interact in heterotypic and heteromeric configurations both in vivo and in expression systems (White et al. 1994 Jiang and Goodenough 1996 Hopperstad et al. 2000).

Demonstration of mechanisms underlying the specificity of connexin intercellular channels in these contexts is still missing. It was shown that fiber𠄿iber conductance was lower in the Cx50 46/46 knockin than WT (Martinez-Wittinghan et al. 2004), thus the knockin approach may provide equal numbers of channels but does not provide equal levels of coupling. Regardless, the relationship between coupling level and differential mitotic rates remains obscure. We favor the notion that differential permeability of intercellular channels may play a more important role, as connexin-dependent differences in small molecule permeability have been observed in several studies (Harris 2007). For example, Cx43 channel permeability to cAMP is approximately three times higher than Cx26 and approximately five times higher than Cx40 (Kanaporis et al. 2008), providing a conceptual framework for the observed differences in knockin phenotypes (Harris 2008).

Gap Junctions in Myelin and the Central Nervous System

Mutations in Cx32 associated with the X-linked form of Charcot-Marie-Tooth syndrome result in a peripheral neuropathy associated with myelin failure in Schwann cells. Cx32 forms “reflexive” gap junctions that the Schwann cell makes with itself at the paranodal membranes and incisures of Schmidt-Lantermann. This anatomy suggests that the reflexive junctions in myelin are essential for communication between perinuclear and adaxonal Schwann cell cytoplasm. Measurements of the rate of diffusion between these two cytoplasmic compartments in individual Schwann cells support this notion (Balice-Gordon et al. 1998). However, there is no significant difference between diffusion rates in WT and Cx32 KO animals. To explain this discrepancy, it was hypothesized that Cx29, which is equally abundant although with a somewhat different intracellular distribution, might substitute for the loss of Cx32. However, Cx29 does not accumulate in gap junctional plaques in vivo in oligodendrocytes or Schwann cells (Altevogt et al. 2002 Nagy et al. 2003 Altevogt and Paul 2004) or form function gap junctions when expressed in tissue culture cells (Altevogt et al. 2002). On the other hand, the Cx29 KO does show a myelin defect but one that is restricted to cell bodies of the spiral ganglion neurons in the organ of Corti (Tang et al. 2006).

An additional surprising role for connexins has been shown in the developing neocortex (Elias et al. 2007). Cx26 and Cx43 protein expression was substantively knocked down by electroporation of shRNAs into E16 embryonic cortex. Connexin knockdown resulted in the stalling of migration of neurons along radial glia in the intermediate zone and a loss of cells arriving in the lower and upper cortical plates. Further experiments showed that normal migration was dependent on neuronal rather than glial expression of connexins (Elias et al. 2007). Connexin knockdown neurons showed normal timing of exit from mitosis and no detectable changes in apoptosis, which is unexpected because changes in cell�ll communication and hemichannel involvement in Ca 2+ waves have been correlated with stages of the mitotic cycle (Bittman et al. 2007). Surprisingly, a channel-dead mutant (Beahm et al. 2006) rescued the migration defect, whereas mutations that resulted in both the loss of connexon pairing (but not hemichannel activity) and the loss of interaction with cytoplasmic partners (C-terminal truncations) were unable to rescue (Elias et al. 2007). These data led to the conclusion that the adhesive properties of connexins, rather than channel activity, were required for correct neuronal migration. In this context, it is of interest that Cx43 hemichannels can confer adhesivity between HeLa and C6 glioma cells in culture (Cotrina et al. 2008).

In summary, connexins and innexins are universally used to promote intercellular interactions between cells in solid tissues and circulating elements of the blood (Wong et al. 2006). They show multiple levels of regulation from instantaneous to hours. Genetic studies have shown that gap junctions are involved in a wide variety of functions in homeostasis, regulation, regeneration, and development. Given that a complex spectrum of small molecules within a cell can potentially diffuse through gap-junctional channels into neighbors, the identification of the relevant small molecules subserving each function has been difficult. Connexons, the hexameric precursor to the gap-junction channel, can function as a hemichannel in nonjunctional membranes promoting paracrine signaling. Even without channel function, the adhesivity of connexons can provide critical migratory cues. Unraveling the multiple functions of connexins and innexins and the contributions to these functions controlled by channel selectivity and regulation, is fundamental to understanding many aspects of collective cellular behavior.


Plasticity of Retinal Gap Junctions: Roles in Synaptic Physiology and Disease

Electrical synaptic transmission via gap junctions underlies direct and rapid neuronal communication in the central nervous system. The diversity of functional roles played by electrical synapses is perhaps best exemplified in the vertebrate retina, in which gap junctions are expressed by each of the five major neuronal types. These junctions are highly plastic they are dynamically regulated by ambient illumination and circadian rhythms acting through light-activated neuromodulators. The networks formed by electrically coupled neurons provide plastic, reconfigurable circuits positioned to play key and diverse roles in the transmission and processing of visual information at every retinal level. Recent work indicates gap junctions also play a role in the progressive cell death and aberrant activity seen in various pathological conditions of the retina. Gap junctions thus form potential targets for novel neuroprotective therapies in the treatment of neurodegenerative retinal diseases such as glaucoma and ischemic retinopathies.

Keywords: connexins electrical synapses gap junctions neurodegeneration retina.


Rectifying electrical synapses in pattern-generating circuits

Rectifying electrical synapses are more interesting than they might seem at first. Our recent study finds that they have the potential to allow a circuit to control how robust the circuit output is to modulation of synaptic strength.

Gap junctions allow neurons to communicate quickly by serving as a direct conduit of electrical signals. Non-rectifying gap junctions probably come to mind first for most neuroscientists when they think about electrical synapses, since they are the idealized textbook variety. The electrical current that passes through the non-rectifying type of gap junction is simply a function of the voltage difference between the coupled neurons. However, this is only the case when the two hemi-channels that form a gap junction pore have the same voltage-dependencies.

Schematic shows that neurons can express diverse gap junction subunits (top left). Rectifying gap junction conductance is a function voltage difference between two neurons (top right). Bottom panel illustrates how coupled neuron output depends on the polarity of the rectifying electrical synapse and the intrinsic properties of the coupled neurons.

We know from past electrophysiology studies that a single neuron can express a diverse set of gap junction hemi-channels, enabling it to form similarly diverse gap junction channels with another neuron. This could result in rectifying electrical synapses in which current flows asymmetrically between neurons so that current flow can either be permitted or restricted depending on whether the current is positive or negative. What we didn’t know were the consequences of electrical synapse rectification for a pattern-generating circuit of competing oscillators. Our recently published study in J. Neuroscience addressed this question and led us to conclude that rectifying electrical synapses can change how a neuronal circuit responds to modulation of its synapses – including its chemical synapses. Although we used a computational model for our study, our results indicate that rectifying electrical synapses in biological networks can be an important component in neuronal circuits that produce rhythmic patterns, such as those found in motor systems.

Gabrielle Gutierrez obtained her PhD in Neuroscience from Brandeis earlier this year, and is currently doing a postdoc with Sophie Deneuve at the Ecole Normale Superieure in Paris

Gutierrez GJ, Marder E. Rectifying electrical synapses can affect the influence of synaptic modulation on output pattern robustness. J Neurosci. 201333(32):13238-48.


Neural connectivity

Numerous studies have shown that neurons are not connected in an anarchic way to each other, but that the relationships between different nerve centers they follow guidelines that transcend a particular animal species, being characteristic of the animal group.

This connectivity between different nerve centers arises during embryonic development and is perfected as it grows and develops. The basic wiring in different vertebrate animals shows a general resemblance, a reflection of gene expression patterns inherited from common ancestors.

During the differentiation of a neuron, its axon develops guided by the chemical characteristics of the structures which were in its stage and these serve as a reference for knowing how to position and position itself within the neural network.

Neural connectivity studies have also shown that there is generally a predictable correspondence between the position of neurons at the center of origin and that of their axons at the center of destination, and accurate topographic maps of the connection can be made between the two. areas.


Electrical Coupling in Caenorhabditis elegans Mechanosensory Circuits

I. Rabinowitch , W.R. Schafer , in Network Functions and Plasticity , 2017

Abstract

Electrical synapses formed by gap junctions are widespread in the human brain as well as in simpler nervous systems. The nematode Caenorhabditis elegans, with its completely mapped connectome of 302 neurons and approximately 4000 electrical synapses, is therefore well suited to investigate the functional importance of electrical coupling in neuronal microcircuits. We have found that hub-and-spoke gap junction circuit in C. elegans mediates the integration of mechanosensory information to control nose touch avoidance behavior. A combination of lateral facilitation between active inputs and inhibitory shunting to inactive inputs implements an analog coincidence detector, a property that might be shared with other hub-and-spoke circuits. We also describe transgenic methods for the synthetic insertion of ectopic gap junctions, which may have broad experimental applications.


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Gap junctions

In vertebrates and invertebrates, signaling among neurons is most commonly mediated by chemical synapses. At these synapses neurotransmitter released by presynaptic neurons is detected by receptors on the postsynaptic neurons, leading to an influx of ions through the receptors themselves or through channels activated by intracellular signaling downstream of the receptors. But neurons can communicate with each other in a more direct way, by passing signals composed of small molecules and ions through pores called gap junctions. Gap junctions that transmit electrical signals are called electrical synapses. Unlike most chemical synapses, electrical synapses interact through axon-to-axon or dendrite-to-dendrite contacts. Found throughout the nervous system, they are probably best known for linking the relatively few inhibitory, GABAergic, neurons into large, effective networks within vertebrate brains. They are particularly important early in development before the formation of most chemical synapses, but recent work shows gap junctions play important roles in the adult nervous system, too. Gap junctions are sometimes thought to be mere passageways between cells. But, as recent work shows, their properties can be complex and surprising. Gap junctions help generate, propagate, and regulate neural oscillations, can filter electrical signals, and can be modulated in a variety of ways. Here we discuss recent work highlighting the diversity and importance of gap junctions throughout the nervous system.


SURPRISING AND PUZZLING RESULTS FROM CONNEXIN MUTATIONS

Other functions that emerge from connexin deletions may result from the loss of a complex interplay of multiple connexin-family members in an incompletely defined network, producing unexpected and unexplained outcomes. Some of these examples are explored here in more detail.

Gap Junctions in the Vascular System

Arterioles are composed of a longitudinal layer of endothelial cells facing the blood, which is separated by a basal lamina from a layer of circular smooth muscle cells that control lumen diameter. There is a surprising complexity of connexin expression in the arteriolar layers. Smooth muscle cells express mainly Cx43 (Gabriels and Paul 1998) and endothelial cells mainly Cx40 (Little et al. 1995 van Kempen and Jongsma 1999), although both cell types express both connexins. Cx32 expression has been reported in endothelial cells (Okamoto et al. 2009). Smooth muscle cells uniquely express Cx45 (Kruger et al. 2000), whereas only the endothelium contains Cx37 (Gabriels and Paul 1998 van Kempen and Jongsma 1999). In addition, there can be significant regional variations in the relative abundance of these connexins in the vessel wall. As an example, endothelial Cx43 is dramatically up-regulated at the expense of the other connexins in areas that experience shear stresses such as vessel branch points (Gabriels and Paul 1998). Not only are gap junctions formed within arteriolar layers, but junctions are also formed between smooth muscle and endothelial cells. The connexin content of the myoendothelial junctions is not yet clear, although in vitro studies suggest that the endothelial side contains largely if not exclusively Cx40 (Isakson and Duling 2005).

Gap junctions have been strongly implicated in the conducted spread of vasodilation. Local endothelial stimulation initiates a rapidly propagated, bidirectional wave of relaxation along the vessel axis (Welsh and Segal 1998 Figueroa et al. 2003 de Wit et al. 2006). An intact endothelium is required for conducted vasodilation, which does not decay with distance and so must contain a self-regenerative component. The propagation of vasomotor activity is significantly depressed in Cx40 KO but not Cx37 KO animals (Figueroa et al. 2003 de Wit et al. 2000). While it was initially surprising that the loss of Cx37, which is co-expressed in endothelial cells, had no effect on propagation, this could be explained by the fact that loss of Cx40 causes a dramatic (㸠-fold) reduction in the levels of endothelial Cx37, while loss of Cx37 results in only a mild (𢏏ourfold) reduction in the levels of Cx40 (Simon and McWhorter 2003).

A simple model for the role of gap junctions in propagation is that endothelial stimulation results in a change in membrane potential that is passively conducted along the endothelial layer through gap junctions, critically those containing Cx40. However, this model does not explain self-propagation. Even more problematic, knockin of Cx45 into the Cx40 locus does not rescue the Cx40 KO phenotype, suggesting that ionic spread of membrane potential changes through endothelial𠄾ndothelial gap junctions is not a critical factor (Wolfle et al. 2007). On the other hand, studies using connexin-mimetic peptides to selectively inhibit junctional communication in rabbit iliac arteries suggest that although Cx40 is required for endothelium-dependent smooth muscle hyperpolarization, Cx43 is required for spread of that hyperpolarization within the smooth muscle layer (Chaytor et al. 2005). Taken together, these observations suggest another model in which propagation requires both myoendothelial gap junctions as well as gap junctions joining smooth muscle cells. In the first phase, endothelial stimulation leads to release of an endothelium-derived hyperpolarizing factor (EDHF), causing hyperpolarization of immediately adjacent smooth muscle. It has been suggested that EDHF signaling requires myoendothelial junctions (Griffith 2007), which are permeable to inositol trisphosphate and Ca 2+ (Isakson et al. 2007). A second phase might involve electrotonic spread of hyperpolarization within the smooth muscle layer through gap junctions composed of Cx43. The extent of this spread would be modest as electrical coupling in this layer is relatively weak. In the third phase, smooth muscle must restimulate endothelial cells distal to the site of initial stimulus, regenerating additional rounds of EDHF release. Relaxation of smooth muscle accompanies release of a second factor, endothelium-derived relaxation factor (likely nitric oxide), which can move from endothelium to smooth muscle in the absence of gap junctions. This model is consistent with the loss of conducted vasodilation in the Cx40 KO, but not Cx37 KO, and predicts a Cx40 KO phenocopy in a smooth muscle-specific Cx43 KO, which has not yet been evaluated.

In addition to vasomotor responses, connexin knockouts can dramatically impact systemic blood pressure. Conditional disruption of Cx43 in vascular endothelial cells results in hypotension and bradycardia (Liao et al. 2001), accompanied by elevated plasma levels of nitric oxide because of increased activity of endothelial nitric oxide synthase. These phenotypes are currently without explanation and are not seen in another model of vascular deletion of Cx43 (Theis et al. 2001). In contrast to the hypotension accompanying vascular loss of Cx43, constitutive deletion of Cx40 results in hypertension (de Wit et al. 2006). In this case, disregulation of angiotensin levels may be responsible. In these animals, renin-producing cells are anatomically displaced during development (Kurtz et al. 2007) and are also less responsive to feedback inhibition by plasma angiotensin, leading to increased plasma levels of renin (Wagner et al. 2007). Why the loss of Cx40 results in this cellular localization defect is not known. Interestingly, although knockin of Cx45 into the Cx40 locus is unable to rescue propagation of the vasomotor activity (Wolfle et al. 2007), it abrogates the hyperreninemia, partially attenuating the systemic hypertension and restoring angiotensin-suppression of renin release (Schweda et al. 2008). Parenthetically, Cx45 deletion from smooth muscle in the juxtaglomerular apparatus later in development also results in increased renin secretion and significant blood pressure elevation (Hanner et al. 2008 Yao et al. 2008).

The double knockout (dKO) of Cx37 and Cx40 displays an additional phenotype not seen in either individual knockout. dKO animals die perinatally with dramatic vascular abnormalities. By E18.5, numerous hemorrhages are visible through the skin and internally in the testes, lungs, and intestines. Vasculogenesis is aberrant in the testis and in the connective tissues of the small bowel, but seemingly unaffected in other organs (Simon and McWhorter 2002 Simon and McWhorter 2003). It is not known if these new pathologies result from a combination of the individual regulation and selectivities of the individual connexins, or if this is because of unique properties exhibited by heteromeric or heterotypic intercellular channels.

Gap Junctions in the Ocular Lens

During development, the optic vesicle induces the overlying ectoderm to invaginate and pinch off a hollow sphere of cells, the lens vesicle. The posterior cells of the vesicle then elongate anteriorly as lens fibers, which contact the anterior cells occluding the vesicle lumen. The lens thus becomes a solid cyst of cells, with an anterior epithelium and posterior fibers. The organ eventually loses an enveloping basket of blood vessels, becoming totally avascular and therefore dependent on the aqueous humor for all metabolic needs. The lens continues to grow in volume throughout the life of the organism by appositional growth, differentiating new lens fibers from a stem cell population at the equatorial surface. The older fibers do not turn over, remaining in the lens interior. To achieve a high refractive index and transparency, the differentiating fibers synthesize high concentrations of soluble proteins, the crystallins, and then undergo a limited apoptosis, destroying their nuclei and all light-scattering organelles. Thus, the lens fibers are metabolically dependent on the anterior epithelial cells that retain their organelles. The lens fibers are joined to each other and to the epithelial cells by large numbers of gap junctions (Goodenough 1992). The asymmetric location of the Na + K + ATPase in the epithelium results in a translenticular potential and a DC current flow (Candia et al. 1970), modeled as the circulatory system of the lens (Rae 1979 Mathias 1985 Mathias and Rae 1989). As the high concentration of the crystallins requires a tight control of ionic balance to remain in solution, the ionic syncytium created by the gap junctions is essential for lens transparency.

Cx43, 46, and 50 are expressed in the lens. Cx43 and 50 are found abundantly in the lens epithelium (Beyer et al. 1987 Jiang et al. 1995 Martinez-Wittinghan et al. 2003). Cx46 and 50 are found joining the lens fibers where they colocalize to the same junctional plaques (Paul et al. 1991) and have been shown to co-oligomerize into the same connexons and intercellular channels (Konig and Zampighi 1995 Jiang and Goodenough 1996). Indeed, immunofluorescence studies have shown colocalization of Cx46 and 50 in all junctional plaques joining the fibers. Given this anatomical overlap, it is surprising that targeted deletion of Cx46 and 50 result in distinctly different phenotypes (Gong et al. 1997 White et al. 1998). First, both cause cataracts but with differences in timing of onset and in morphology. Second, deletion of Cx50, but not Cx46, results in a slower postnatal growth rate with concomitant decrease in lens size and microphthalmia (White et al. 1998). Interestingly, the normal growth rate is uniquely dependent on Cx50 because replacing the coding region of Cx50 with that of Cx46 (Cx50 46/46 ) does not fully rescue the lens mitotic rate (White 2002 Sellitto et al. 2004). The identity of the Cx50-dependent signal controlling mitosis is not known (White et al. 2007). The Cx46/Cx50 double knockout shows a phenotype more severe but predictable as the sum of the two individual connexin deletions (Xia et al. 2006).

Cx50 46/46 animals are completely free of cataracts (White 2002), suggesting that this pathology could be prevented by simply restoring adequate numbers of junctional channels. Thus, it is surprising that mice heterozygous for Cx46 and Cx50 at the Cx50 locus (Cx50 +/46 ) develop a cataract (Martinez-Wittinghan et al. 2003). Furthermore, this cataract is morphologically different from those in either Cx46KO or Cx50KO lenses. Although the latter two are primarily nuclear, the Cx50 +/46 cataract is largely subepithelial. Additional crosses show that the Cx50 +/46 cataract is insensitive to dosage of Cx46 at the Cx46 locus, proving that this unexpected phenotype is the result of changes in connexin stoichiometry in the epithelium, where Cx46 is not normally detected. Importantly, the phenotype only occurs when Cx50 and Cx46 are coexpressed in the epithelium, because no cataract is observed in the homozygous (Cx50 46/46 ) knockin (White 2002). In addition to the cataract, Cx50 +/46 lenses display impaired dye transfer both within the epithelial plane and between epithelium and underlying fibers (Martinez-Wittinghan et al. 2003). Why mixing of Cx46 and Cx50 in the epithelium should depress dye transfer and cause a novel cataract is completely without explanation because those connexins functionally interact in heterotypic and heteromeric configurations both in vivo and in expression systems (White et al. 1994 Jiang and Goodenough 1996 Hopperstad et al. 2000).

Demonstration of mechanisms underlying the specificity of connexin intercellular channels in these contexts is still missing. It was shown that fiber𠄿iber conductance was lower in the Cx50 46/46 knockin than WT (Martinez-Wittinghan et al. 2004), thus the knockin approach may provide equal numbers of channels but does not provide equal levels of coupling. Regardless, the relationship between coupling level and differential mitotic rates remains obscure. We favor the notion that differential permeability of intercellular channels may play a more important role, as connexin-dependent differences in small molecule permeability have been observed in several studies (Harris 2007). For example, Cx43 channel permeability to cAMP is approximately three times higher than Cx26 and approximately five times higher than Cx40 (Kanaporis et al. 2008), providing a conceptual framework for the observed differences in knockin phenotypes (Harris 2008).

Gap Junctions in Myelin and the Central Nervous System

Mutations in Cx32 associated with the X-linked form of Charcot-Marie-Tooth syndrome result in a peripheral neuropathy associated with myelin failure in Schwann cells. Cx32 forms “reflexive” gap junctions that the Schwann cell makes with itself at the paranodal membranes and incisures of Schmidt-Lantermann. This anatomy suggests that the reflexive junctions in myelin are essential for communication between perinuclear and adaxonal Schwann cell cytoplasm. Measurements of the rate of diffusion between these two cytoplasmic compartments in individual Schwann cells support this notion (Balice-Gordon et al. 1998). However, there is no significant difference between diffusion rates in WT and Cx32 KO animals. To explain this discrepancy, it was hypothesized that Cx29, which is equally abundant although with a somewhat different intracellular distribution, might substitute for the loss of Cx32. However, Cx29 does not accumulate in gap junctional plaques in vivo in oligodendrocytes or Schwann cells (Altevogt et al. 2002 Nagy et al. 2003 Altevogt and Paul 2004) or form function gap junctions when expressed in tissue culture cells (Altevogt et al. 2002). On the other hand, the Cx29 KO does show a myelin defect but one that is restricted to cell bodies of the spiral ganglion neurons in the organ of Corti (Tang et al. 2006).

An additional surprising role for connexins has been shown in the developing neocortex (Elias et al. 2007). Cx26 and Cx43 protein expression was substantively knocked down by electroporation of shRNAs into E16 embryonic cortex. Connexin knockdown resulted in the stalling of migration of neurons along radial glia in the intermediate zone and a loss of cells arriving in the lower and upper cortical plates. Further experiments showed that normal migration was dependent on neuronal rather than glial expression of connexins (Elias et al. 2007). Connexin knockdown neurons showed normal timing of exit from mitosis and no detectable changes in apoptosis, which is unexpected because changes in cell�ll communication and hemichannel involvement in Ca 2+ waves have been correlated with stages of the mitotic cycle (Bittman et al. 2007). Surprisingly, a channel-dead mutant (Beahm et al. 2006) rescued the migration defect, whereas mutations that resulted in both the loss of connexon pairing (but not hemichannel activity) and the loss of interaction with cytoplasmic partners (C-terminal truncations) were unable to rescue (Elias et al. 2007). These data led to the conclusion that the adhesive properties of connexins, rather than channel activity, were required for correct neuronal migration. In this context, it is of interest that Cx43 hemichannels can confer adhesivity between HeLa and C6 glioma cells in culture (Cotrina et al. 2008).

In summary, connexins and innexins are universally used to promote intercellular interactions between cells in solid tissues and circulating elements of the blood (Wong et al. 2006). They show multiple levels of regulation from instantaneous to hours. Genetic studies have shown that gap junctions are involved in a wide variety of functions in homeostasis, regulation, regeneration, and development. Given that a complex spectrum of small molecules within a cell can potentially diffuse through gap-junctional channels into neighbors, the identification of the relevant small molecules subserving each function has been difficult. Connexons, the hexameric precursor to the gap-junction channel, can function as a hemichannel in nonjunctional membranes promoting paracrine signaling. Even without channel function, the adhesivity of connexons can provide critical migratory cues. Unraveling the multiple functions of connexins and innexins and the contributions to these functions controlled by channel selectivity and regulation, is fundamental to understanding many aspects of collective cellular behavior.


  • Stereotypy
  • stereotypical
  • nodes of Ranvier
  • dendrite
  • olfactory
  • myelination
  • autism
  • plastic
  • glia
  • myelin
  • blood-brain barrier
  • glial cell
  • axon
  • stereotyped
  • apoptosis
  • nodes of ranvier
  • stimuli
  • neurotransmitter
  • neuron

Mechanics of the Action Potential

  • The synapse is the junction where neurons trade information.
  • The stages of an electrical reaction at a synapse are as follows:
  • Chemical synapses are much more complex than electrical synapses, which makes them slower, but also allows them to generate different results.
  • Electrical synapses are faster than chemical synapses because the receptors do not need to recognize chemical messengers.
  • Long-term changes can be seen in electrical synapses.

Neuroplasticity

  • Learning takes place when there is either a change in the internal structure of neurons or a heightened number of synapses between neurons.
  • At birth, there are approximately 2,500 synapses in the cerebral cortex of a human baby.
  • By three years old, the cerebral cortex has about 15,000 synapses.
  • Apoptosis occurs during early childhood and adolescence, after which there is a decrease in the number of synapses.
  • The selection of the pruned neurons follows the "use it or lose it" principle, meaning that synapses that are frequently used have strong connections, while the rarely used synapses are eliminated.

Neurotransmitters

  • Neurotransmitters are chemicals that transmit signals from a neuron across a synapse to a target cell.
  • Neurotransmitters are chemicals that transmit signals from a neuron to a target cell across a synapse.
  • There are several systems of neurotransmitters found at various synapses in the nervous system.
  • Amino acid neurotransmitters are eliminated from the synapse by reuptake.
  • Neuropeptides are often released at synapses in combination with another neurotransmitter.

Cognitive Development in Childhood

  • Once nerve cells in the brain are in place, they form synapses.
  • These synapses release neurotransmitters, which are chemical signals that help the brain communicate.
  • Synapses evolve rapidly, and in doing so, some synapses will die off to make room for new or more important ones.
  • This process improves message transfer between synapses and assists in brain development.
  • Synapses, or the spaces between nerve cells, develop rapidly during childhood.

Habituation, Sensitization, and Potentiation

  • One way that the nervous system changes is through potentiation, or the strengthening of the nerve synapses (the gaps between neurons).
  • In neural communication, a neurotransmitter is released from the axon of one neuron, crosses a synapse, and is then picked up by the dendrites of an adjacent neuron.
  • During habituation, fewer neurotransmitters are released at the synapse.
  • This image shows the way two neurons communicate by the release of the neurotransmitter from the axon, across the synapse, and into the dendrite of another neuron.
  • Communication between neurons occurs when the neurotransmitter is released from the axon on one neuron, travels across the synapse, and is taken in by the dendrite on an adjacent neuron.

Introducing the Neuron

  • The synapse is the chemical junction between the axon terminals of one neuron and the dendrites of the next.
  • One neuron's axon will connect chemically to another neuron's dendrite at the synapse between them.
  • Electrically charged chemicals flow from the first neuron's axon to the second neuron's dendrite, and that signal will then flow from the second neuron's dendrite, down its axon, across a synapse, into a third neuron's dendrites, and so on.
  • Dendrites, cell bodies, axons, and synapses are the basic parts of a neuron, but other important structures and materials surround neurons to make them more efficient.
  • The interface between a motor neuron and muscle fiber is a specialized synapse called the neuromuscular junction.

Basic Principles of Classical Conditioning

  • However, since these pathways are being activated at the same time as the other neural pathways, there are weak synapse reactions that occur between the auditory stimuli and the behavioral response.
  • Over time, these synapses are strengthened so that it only takes the sound of a buzzer to activate the pathway leading to salivation.

Other Steps

  • An electrical impulse crosses a synapse between neurons in the brain, releasing a neurotransmitter.
  • Dendrites, which are extensions of neurons, receive the impulse and allow the synapse to increase in strength this is known as long-term potentiation.

Neural Networks

  • The basic kinds of connections between neurons are chemical synapses and electrical gap junctions, through which either chemical or electrical impulses are communicated between neurons.
  • The method through which neurons interact with neighboring neurons usually consists of several axon terminals connecting through synapses to the dendrites on other neurons.
  • Neurons interact with other neurons by sending a signal, or impulse, along their axon and across a synapse to the dendrites of a neighboring neuron.

Basic Principles of Classical Conditioning: Pavlov

  • However, because these pathways are being activated at the same time as the other neural pathways, there are weak synapse reactions that occur between the auditory stimulus and the behavioral response.
  • Over time, these synapses are strengthened so that it only takes the sound of a buzzer (or a bell) to activate the pathway leading to salivation.
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Contents

The function of neurons depends upon cellular polarization. The distinctive structure of nerve cells allows action potentials to travel directionally (from dendrites to axons), and for these signals to then be received and carried on by post-synaptic neurons or received by effector cells. Nerve cells have long been used as models for cellular polarization, and of particular interest are the mechanisms underlying the polarized localization of synaptic molecules. PIP2 signalling regulated by IMPase plays an integral role in synaptic polarity.

Phosphoinositides (PIP, PIP2, and PIP3) are molecules that have been shown to affect neuronal polarity. Ε] They are synthesized by combinational phosphorylation of phosphatidylinositol (PI), a phospholipid cell membrane component. PI is derived from myo-inositol, which is obtained via three pathways: uptake from the extracellular environment, synthesis from glucose, and the recycling of phosphoinositides. Both the synthesis of myo-inositol from glucose and the recycling of phosphoinositides require myo-inositol monophosphatase – IMPase – an enzyme that produces inositol by dephosphorylating inositol phosphate. Ζ] IMPase has been studied in vivo at some length due to its relevance in the study of bipolar disorder resulting from its sensitivity to lithium. Η] In 2006, a gene (ttx-7) was identified in Caenorhabditis elegans that encodes IMPase. Organisms with mutant ttx-7 genes demonstrated behavioral and localization defects, which were rescued by expression of IMPase and application of inositol. Wild type organisms treated with lithium displayed similar defects to those exhibited by the ttx-7 mutants. This led to the conclusion that IMPase is required for the correct localization of synaptic protein components. ⎖]

The egl-8 gene encodes a homolog of phospholipase Cβ (PLCβ), an enzyme that cleaves PIP2. When ttx-7 mutants also had a mutant egl-8 gene, the defects caused by the faulty ttx-7 gene were largely reversed this suggests that an accumulation of PIP2 corrected the adverse effects of the mutant ttx-7 gene. Furthermore, a mutation in the unc-26 gene (encoding a protein that dephosphorylates PIP2) suppressed the synaptic defects in the ttx-7 mutants. The egl-8 mutants were resistant to lithium treatment. This is genetic evidence that disruption of IMPase alters the levels of PIP2 in neurons these results suggest that PIP2 signaling establishes polarized localization of synaptic components in living neurons. Ζ]