ReviewGap junctions in developing neocortex: a review
Introduction
Gap junction (GJ) channels are a direct route of communication between the cytoplasms of cells. As reviewed in other contributions to this issue, the typical GJ channel is formed by the apposition of two connexons, each in the membrane of one cell, and formed by six connexins, in a toroid structure [43]. Connexons may have only one type of connexins (homomeric connexons), or several (heteromeric) and the GJ can be formed by two identical (homotypic) or different connexons (heterotypic). GJs are present in most tissues, in some serving a metabolic function (liver), in others with a clear electrical connecting function (heart). In the nervous system, after the discovery that neurons were independent units [75], [87], and of the chemical communication between them [23], this was assumed to be the rule. Nevertheless, in invertebrates and lower vertebrates, the importance of GJs was soon recognized as a form of interneuronal communication [6], [24], [100], and the term electrical synapse was established (for review, see Ref. [5]). GJs were also found in the mammalian nervous system [2], [42], [88], but being reportedly scarcer than chemical synapses. This may not be the scenario during early cortical development [49], [104].
Chemical and electrical synapses have important differences. Chemical synapses have an enormous possibility of direct modulation by molecules present in the extracellular milieu, while the electrical, which present a close apposition of the two plasmatic membranes [6], are prone to modulation through the intracellular milieu. Chemical transmission is mostly unidirectional, while the electrical only in some cases shows some electrical rectification. Chemical transmission uses transmitter release, which can amplify the message sent from one neuron to many other ones, while electrical transmission relies on electrotonic propagation. Finally electrical synapses permit the direct passage of molecules from cytosol to cytosol. Thus, it appears that these two ways of communication probably have different functions (or a different way of accomplishing them), and so it is not strange to find them in different places or at different times. During early development, chemical synapses are sparse and the GJs might enable the neurons to communicate with each other, probably with a different message and even a different language, more metabolic than electrical [39]. At this stage, the problems that these neurons have to solve are proliferation, the timing of their migration to the cortical plate or the final position in it. Once these developmental phases are resolved, the chemical synapses might probably be more suited to process the information from outside the brain or other parts of the brain, establishing the appropriate circuits.
The transition from one type of communication to the other would be expected to happen by some kind of modulation between them. Indeed, it has been demonstrated that in the developing cortex GJs can be modulated by different neurotransmitters such as dopamine [84], serotonin [81] and glutamate [39]. In the other direction, although so far only shown in glial cells, the level of expression of some connexins can regulate the release of ATP [17]. As the nervous system matures some connexins remain, and its electrical language becomes important to the coordination of neuronal activity [27], [30].
Section snippets
Different approaches to the study of GJs
Advances in the understanding of the role of the GJs have derived from the progress in the techniques used. Here we analyze the results of different approaches used to study this exciting field and review the role of GJs in early cortical development. Tools to study the GJs include (i) molecular techniques revealing connexins expression at the protein or mRNA level, (ii) tracer coupling, (iii) imaging of intracellular calcium concentration or (iv) recording the communication by
Discussion
Here we will present a unified phenomenology that agrees with the evidence reviewed. During neurogenesis there is a coupling in clusters of cells in the VZ, which includes the radial glia and neural precursors. The size of these clusters decreases from E15 to E19 parallel to the decrease in expression of Cx26 and 43. In the postnatal period, coupling between neurons has an evolution similar to Cx26 and Cx36 expressions, although the latter is maintained in the coupling between interneurons. In
Acknowledgements
This work was funded by the Fulbright Commission, the NEI, the NINDS, the John Merck Fund and the Ministry of Education, Culture and Sports of Spain.
References (105)
- et al.
Expression of connexin36 in the adult and developing rat brain
Brain Res
(2000) Electrical synapses, a personal perspective (or history)
Brain Res. Rev
(2000)- et al.
New dopaminergic terminal fields in the motor, visual (area 18b) and retrosplenial cortex in the young and adult rat. Immunocytochemical and catecholamine histochemical analyses
Neuroscience
(1985) - et al.
Gap junctional communication among developing and injured motor neurons
Brain Res. Rev
(2000) - et al.
Synchronous activity of inhibitory networks in neocortex requires electrical synapses containing connexin36
Neuron
(2001) - et al.
Gap junctions in cultured astrocytes: single-channel currents and characterization of channel-forming protein
Neuron
(1991) - et al.
Gap junctional communication and development
TINS
(1989) - et al.
Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice
Neuron
(2001) - et al.
Neuronal coupling and uncoupling in the developing nervous system
Curr. Opin. Neurobiol
(1995) Coordinate activity in retinal and cortical development
Curr. Opin. Neurobiol
(1993)
The gap junction communication channel
Cell
Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis
Dev. Brain Res
Development of the noradrenergic innervation of neocortex
Brain Res
GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis
Neuron
Spatiotemporal transcription of connexin45 during brain development results in neuronal expression in adult mice
Neuroscience
The development of beta-adrenergic receptors in the visual cortex of the rat
Neuroscience
Cell signaling by second messenger waves
Cell
Reciprocal expression of cell–cell coupling and voltage-dependent Na current during embryogenesis of rat telencephalon
Dev. Brain Res
Gap junctional communication in the developing central nervous system
Cell Biol. Int
Extensive dye coupling between rat neocortical neurons during the period of circuit formation
Neuron
Development of astrocytes and neurons in cultured brain slices from mice lacking connexin43
Dev. Brain Res
Time-related changes in connexin mRNA abundance in the rat neocortex during postnatal development
Dev. Brain Res
Neurotransmitters and gap junctions in developing neural circuits
Brain Res. Rev
Gap junctions between dendrites in the primate neocortex
Brain Res
Many diverse types of retinal neurons show tracer coupling when injected with biocytin or Neurobiotin
Neurosci. Lett
Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32
J. Neurosci
Electrotonic coupling between neurones in the rat mesencephalic nucleus
J. Physiol
Voltage-gated currents, dye and electrical coupling in the embryonic mouse neocortex
Cereb. Cortex
Electrotonic junctions between teleost spinal neurons: electrophysiology and ultrastructure
Science
Connexin mutations in X-linked Charcot–Marie–Tooth disease
Science
Differential regulation of connexin 26 and 43 in murine neocortical precursors
Cereb. Cortex
Cell coupling and uncoupling in the ventricular zone of developing neocortex
J. Neurosci
Connexin expression in homotypic and heterotypic cell coupling in the developing cerebral cortex
J. Comp. Neurol
The formation and maturation of synapses in the visual cortex of the rat: II. Quantitative analysis
J. Neurocytol
Potentiated opioid analgesia in norepinephrine transporter knock-out mice
J. Neurosci
Cellular expression of connexins in the rat brain: neuronal localization, effects of kainate-induced seizures and expression in apoptotic neuronal cells
Eur. J. Neurosci
Coupling between neurons of the developing rat neocortex
J. Neurosci
Connexins regulate calcium signaling by controlling ATP release
Proc. Natl. Acad. Sci. U. S. A
Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas
Proc. Natl. Acad. Sci. U. S. A
Differential expression of three gap junction proteins in developing and mature brain tissues
Proc. Natl. Acad. Sci. U. S. A
Oligodendrocytes express gap junction proteins connexin32 and connexin45
Glia
Electrotonic coupling in the inferior olivary nucleus revealed by simultaneous double patch recordings
J. Neurophysiol
An analysis of the end-plate potential recorded with an intracellular electrode
J. Physiol
Transmission at the giant motor synapses of the crayfish
J. Physiol
Changes in neuronal migration in neocortex of connexin43 null mutant mice
J. Neuropathol. Exp. Neurol
Transplacental uptake of glucose is decreased in embryonic lethal connexin26-deficient mice
J. Cell Biol
Electrical synapses between GABA-releasing interneurons
Nat. Rev., Neurosci
Large-scale oscillatory calcium waves in the immature cortex
Nat. Neurosci
Two networks of electrically coupled inhibitory neurons in neocortex
Nature
Connexins, connexons, and intercellular communication
Annu. Rev. Biochem
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