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Expression and functions of neuronal gap junctions

Nature Reviews Neuroscience volume 6, pages 191–200 (2005)Cite this article

Key Points

  • Gap-junctional communication between neurons was first described several decades ago in crayfish, and was later studied by electrophysiological means in mammals. This field of research gained new momentum when the connexin 36 (Cx36) gene was discovered and its neuronal expression characterized.

  • It is now clear that gap junctions between neurons (also called electrical synapses) are abundant postnatally and are even expressed in certain areas of the adult brain, including the retina. They seem to fulfil distinct functions that are independent of, but possibly modulated by, chemical synapses.

  • In addition to Cx36, Cx45 and Cx57 expression have also been shown in certain types of mouse neuron. Recently, pannexin 1 and 2 were also shown to be expressed in certain types of central neuron in rodents and to form gap junction channels — at least after exogenous expression — in Xenopus laevis oocytes.

  • Identification of the expression pattern of connexins in neurons was greatly eased by analysis with reporter genes, which can be expressed in trangenic mice instead of the corresponding connexin gene.

  • During recent years, neuronal gap junctions have been characterized or postulated to be expressed in several adult brain regions, including the neocortex, thalamus, inferior olive, cerebellum and retina.

  • The characterization of transgenic mouse mutants deficient in CX36 showed that gamma frequency network oscilliations between hippocampal interneurons were disrupted in such mutants and that night vision was compromised. The same decrease in the b-wave in the electroretinogram was found in CX36-deficient mice and in neuronally CX45-deficient mice, which, together with immunochemical evidence, indicates that these connexins form heterotypic gap junction channels between AII amacrine cells and ON-cone bipolar cells.

Abstract

Gap junctions are channel-forming structures in contacting plasma membranes that allow direct metabolic and electrical communication between almost all cell types in the mammalian brain. At least 20 connexin genes and 3 pannexin genes probably code for gap junction proteins in mice and humans. Gap junctions between murine neurons (also known as electrical synapses) can be composed of connexin 36, connexin 45 or connexin 57 proteins, depending on the type of neuron. Furthermore, pannexin 1 and 2 are likely to form electrical synapses. Here, we discuss the roles of connexin and pannexin genes in the formation of neuronal gap junctions, and evaluate recent functional analyses of electrical synapses that became possible through the characterization of mouse mutants that show targeted defects in connexin genes.

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Figure 1: Molecular organization and schematic topology of a gap-junctional plaque.
Figure 2: Distribution of Cx45/LacZ and Cx36/LacZ expression in the adult mouse brain.
Figure 3: Pattern of reporter gene expression for Cx36, Cx45 and Cx57 in the retina of connexin-deficient mice.
Figure 4: Gap junction coupling in the main types of neuron in the mouse retina.

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Acknowledgements

Work in our laboratory was supported by grants from the German Research Association to K.W.

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  1. Abteilung Molekulargenetik, Institut für Genetik, Universität Bonn, Römerstrasse 164, Bonn, 53117, Germany

    Goran Söhl, Stephan Maxeiner & Klaus Willecke

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  1. Goran Söhl
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Correspondence to Klaus Willecke.

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DATABASES

Entrez Gene

CX32

CX36

CX43

CX45

CX57

PX1

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Glossary

LOW-PASS FILTER

A low-pass filter preferentially allows the transmission of low-frequency stimuli and the transfer of sub-threshold potentials that favour synchronous activity. Low-pass filter characteristics of electrical synapses are a consequence of the conductance of gap junction channels feeding into the parallel capacitance and conductance of the postsynaptic cell.

MAUTHNER CELLS

A bilateral pair of brainstem neurons, characteristic of fish, that receive acoustic information and trigger an escape response.

OLIVOCEREBELLAR COMPLEX

A functional unit of the inferior olive and cerebellum. Interactions between the cerebellum and inferior olive contribute to the acquisition and extinction of the eyeblink.

LEAK CONDUCTANCE

Leak conductance in gap junctions means that these channels might allow the flow or exchange of small currents from cell to cell, therefore lowering their input resistance.

HARMALINE TREMOR

In animals, harmaline injections trigger oscillatory activity in the inferior olive, which is accompanied by a tremor of the same frequency (4–12 Hz). This harmaline-induced tremor seems to be similar, in many aspects, to the tremor seen in patients with Parkinson's disease.

BASKET CELLS

Inhibitory interneurons located in the molecular layer of the cerebellum. Basket cells are located close to Purkinje cells and spread out horizontally.

STELLATE CELLS

Inhibitory interneurons located in the molecular layer of the cerebellum. Stellate cells are symmetrical in shape and their processes radiate from the cell body.

GAMMA AND THETA OSCILLATIONS

Oscillatory activity of specific frequency bands in distinct brain regions correlates with distinct behavioural states. During awake as well as active periods and REM sleep, theta (4–12 Hz) and gamma (20–90 Hz) oscillations are prevalent and are thought to involve interneurons as well as principal cells.

HIGH-FREQUENCY OSCILLATIONS

(HFOs). When mice or rats are immobile and awake, or in the non-REM phase of sleep, the so-called 'ripple' oscillations or high-frequency oscillations (in the range of 100–600 Hz) can be measured. Recent evidence indicates that ripples have a specific role in memory processing.

SPIKELETS

(Also known as d-spikes or fast pre-potentials). Brief low-amplitude potentials that have the appearance of action potentials but are much smaller. Spikelets are widely considered to be the electrophysiological correlate of electrotonic coupling through gap junctions.

STRATUM ORIENS

The stratum oriens is located between the alveus and the pyramidal cell layer of the hippocampus. Besides some astrocytes and interneurons, it mainly consists of axon bundles from CA1 pyramidal cells.

Cre/LoxP RECOMBINATION

A site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre-recombinase enzyme catalyses recombination between the loxP sites, leading to excision of the intervening sequence.

THALAMOCORTICAL CIRCUITRY

This distinct circuitry might underlie the capacity of the cortex to induce or maintain thalamocortical synchrony.

THALAMIC OSCILLATIONS

During relaxed wakefulness, thalamic oscillations in the human electroencephalogram mainly consist of alpha (∼8–13 Hz) oscillations, which, with the onset of drowsiness, are briefly replaced by slower theta (∼2–7 Hz) oscillations, prior to the onset of spindle (7–14 Hz) and slow-wave (<1 Hz) oscillations during sleep.

BIPOLAR CELLS

Bipolar cells receive information formed by the interactions of horizontal cells with cone or rod photoreceptors and convey it to the inner retina. ON (cone or rod) bipolar cells respond to increases in intensity, whereas OFF (cone and rod) bipolar cells respond to decreases in intensity.

HORIZONTAL CELLS

Horizontal cells form a network of interconnecting retinal neurons just beneath the photoreceptors (that is, the photoreceptor cells), which is responsible for averaging visual activity over space and time, as well as controlling the gain and offset of the photoreceptor signal.

GANGLION CELLS

Output neurons of the retina, the axons of which form the optic nerve. ON ganglion cells respond to increases in intensity, whereas OFF ganglion cells respond to decreases in intensity.

AII AMACRINE CELLS

A subtype of retinal amacrine cell with a small dendritic field that conveys the rod signal to cone bipolar cells.

RECEPTIVE FIELD

A dynamic area of the retina in which stimulus presentation leads to the response of a particular ganglion cell.

EPHAPTIC TRANSMISSION

Ephaptic transmission or interaction through electrical field effects is a direct electrotonic transfer of excitation from one unit to the next. The ephapse is a site where two or more nerve cell processes (axons or dendrites) touch without forming a typical synaptic contact.

HEMICHANNELS

[In horizontal cells]. Hemichannels could depolarize cone pedicles and subsequently activate voltage-gated Ca2+ channels. This could lead to glutamate release, which would convey a 'feedback' response appropriate for a decrease in light-induced signals that are transmitted forward by bipolar and ganglion cells.

RIBBON SYNAPSE

Synapses characterized by an electron-dense ribbon or bar in the presynaptic terminal. The ribbon is commonly oriented at a right angle to the membrane and sits just above an evaginated ridge. It is thought that the ribbons help to guide vesicles to the release sites. Ribbon synapses are commonly found in the retinae and cochlea of vertebrates.

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Söhl, G., Maxeiner, S. & Willecke, K. Expression and functions of neuronal gap junctions. Nat Rev Neurosci 6, 191–200 (2005). https://doi.org/10.1038/nrn1627

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