Trends in Neurosciences
Volume 23, Issue 2, 1 February 2000, Pages 68-74
Journal home page for Trends in Neurosciences

Review
Gap junctions, synchrony and seizures

https://doi.org/10.1016/S0166-2236(99)01497-6Get rights and content

Abstract

The old concept that the direct intercellular cytoplasmic connections between neurones participate in the coordination of neuronal activity has gained new relevance, owing to recent theoretical and experimental evidence, particularly with regard to neuronal synchronization and epileptogenesis. Computer simulations demonstrating that neurones synchronize and alter their firing patterns depending on gap-junctional communication, have provided insights into the interactions between electrotonic coupling and cellular and synaptic characteristics. Experimental manipulations of gap-junctional communication support its role in the generation and maintenance of synchronized neuronal firing and seizures. Hence, in addition to chemical transmission, direct electrotonic coupling might contribute to normal and abnormal physiological brain rhythms.

Section snippets

The reticulum theory of brain-cell communication

In the 19th century it was thought that the brain was composed of cells that were connected to each other directly to form a ‘reticulum’. Around 1900, experimental observations revealed the brain structure as a network of cells, called neurones1, and the multitudinous connections between them as synapses2. The later discovery of chemical synaptic transmission3 led to a complete shift in emphasis towards the subtleties and variety of the modulatory actions of this most-common form of neuronal

Gap junctions and the regulation of intercellular coupling

Evidence for direct electrical transmission was found first in invertebrate preparations between 1958 and 1959 (9, 10), and later in vertebrate tissue by Bennett and colleagues in 1963 (Ref. 11). In 1971, Baker and Llinás found evidence for electrical transmission in the mammalian brain12 (rat mesencephalic nucleus), and in 1973, Korn and colleagues found electrical interactions in the rat lateral vestibular nucleus13. MacVicar and Dudek were the first to demonstrate, in central mammalian

Simulations, artificial junctions and neuronal synchrony

The idea that gap junctions allow for synchrony of neuronal firing was already recognized in 1958, as hypothesized in the first report that demonstrated neuronal electrotonic interactions directly9. Early studies on the nature of GJC indicated that gap junctions acted as low-pass filters, basically ohmic resistors that connected two cytoplasms30. Hence, slow changes in membrane potentials can be readily transmitted.

Theoretical models have been developed to explain the influence of electrical

Controversial techniques and straight answers

Although the computer-simulated electrical interactions have been discussed above, the question now arises as to whether there are any data to substantiate the theory. A discussion of the techniques used in the investigation of electrotonic transmission through GJs is required because of the controversy surrounding their use and interpretation. The most-direct evidence can be obtained by recording from two coupled cells and showing the passage of current bidirectionally (presuming minimal

Firing synchrony, seizures and electrical interactions: what brains can do without chemical synapses

Synchrony might be desirable in some cases, such as contraction in smooth and cardiac muscle, but it could have pathological consequences in the case of large neuronal populations. Indeed, abnormal hypersynchrony of adjacent neuronal spike firing is a signature of epilepsy. Does electrotonic interaction through GJs promote seizures?

Depolarization waves can be transmitted through a network of coupled cells, owing to the low-pass filter characteristics of GJC. However, neuronal networks in the

Seizures as manifestations of a transient neuronal syncytium

These studies raise new questions: if only small groups of neurones are coupled, how can a whole network be synchronized? A conceivable model is shown in Fig. 4. The experimental and theoretical evidence reviewed in this article indicates that there is no need for a perfectly connected neuronal syncytium for network synchrony to occur, because clusters of neurones could become transiently electrotonically coupled and promote the firing of adjacent clusters as a consequence of the larger

Concluding remarks

In order to clarify the contribution of GJC to seizures and firing synchrony, more-specific tools that change GJC are being developed. These tools will help elucidate what types of GJ are implicated in seizures, so that strategies to target the specific connexins involved can be developed. Such strategies might include using peptides homologous to extracellular loop sequences of connexins, which diminish GJC in chick heart myocytes80 and in aortic smooth muscle81, or using anti-connexin

Acknowledgements

The authors are supported by grants from the Medical Research Council of Canada and the Bloorview Epilepsy Programme.

References (82)

  • R.W. Turner

    Fast pre-potential generation in rat hippocampal CA1 pyramidal neurons

    Neuroscience

    (1993)
  • C.P. Taylor et al.

    A physiological test for electrotonic coupling between CA1 pyramidal cells in rat hippocampal slices

    Brain Res.

    (1982)
  • A. Nuñez

    In vivo electrophysiological analyses of Lucifer yellow coupled hippocampal pyramids

    Exp. Neurol.

    (1990)
  • R.D. Andrew

    Coupling in rat hippocampal slices: dye transfer between CA1 pyramidal cells

    Brain Res. Bull.

    (1982)
  • S.B. Colling

    Dendritic shrinkage and dye-coupling between rat hippocampal CA1 pyramidal cells in the tetanus toxin model of epilepsy

    Brain Res.

    (1996)
  • G.G. Somjen

    Acidification of interstitial fluid in hippocampal formation caused by seizures and spreading depression

    Brain Res.

    (1984)
  • S. Yehuda

    Essential fatty acid preparation (SR-3) raises the seizure threshold in rats

    Eur. J. Pharmacol.

    (1994)
  • T. Hayashi

    Stimulation of cell proliferation and inhibition of gap junctional intercellular communication by linoleic acid

    Cancer Lett.

    (1997)
  • S. Ramón y Cajal

    Histologie du Systeme Nerveux de l’Homme et des Vertebres

    (1911)
  • C.S. Sherrington

    The Integrative Action of the Nervous System

    (1906)
  • O. Loewi

    Problems connected with the principle of humoral transmission of nervous impulses

    Proc. R. Soc. London B Biol. Sci.

    (1933)
  • S.N. Roper

    Increased propensity for nonsynaptic epileptiform activity in immature rat hippocampus and dentate gyrus

    J. Neurophysiol.

    (1993)
  • A. Watanabe

    The interaction of electrical activity among neurones of lobster cardiac ganglion

    Jpn. J. Physiol.

    (1958)
  • E.J. Furshpan et al.

    Transmission at the giant motor synapses of the crayfish

    J. Physiol.

    (1959)
  • M.V.L. Bennett

    Electrotonic junctions between teleost spinal neurones: electrophysiology and ultrastructure

    Science

    (1963)
  • R. Baker et al.

    Electrotonic coupling between neurones in the rat mesencephalic nucleus

    J. Physiol.

    (1971)
  • H. Korn

    Electrotonic coupling between neurones in the rat lateral vestibulat nucleus

    Exp. Brain Res.

    (1973)
  • B.A. MacVicar et al.

    Electrotonic coupling between pyramidal cells: a direct demonstration in rat hippocampal slices

    Science

    (1981)
  • R. Bruzzone

    Connections with connexins: the molecular basis of direct intercellular signalling

    Eur. J. Biochem.

    (1996)
  • D.F. Condorelli

    Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons

    Eur. J. Neurosci.

    (1998)
  • R. Dermietzel

    Differential expression of three gap junctional proteins in the developing and mature brain tissue

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • D.C. Spray

    Physiological properties of gap junction channels in the nervous system

  • D.C. Spray

    Gap junctional conductance is a simple and sensitive function of intracellular pH

    Science

    (1981)
  • B. Rörig

    Dye coupling between pyramidal neurons in developing rat prefontal and frontal cortex is reduced by protein kinase A activation and dopamine

    J. Neurosci.

    (1995)
  • D.G. McMahon

    Modulation of electrical synaptic transmission in zebrafish retinal horizontal cells

    J. Neurosci.

    (1994)
  • J.L. Perez Velazquez

    Neurotransmitter modulation of gap junctional communication in the rat hippocampus

    Eur. J. Neurosci.

    (1997)
  • H. DeVries et al.

    Modulation of an electrical synapse between solitary pairs of catfish horizontal cells by dopamine and second messengers

    J. Physiol.

    (1989)
  • M.V.L. Bennett

    Electrical transmission: a functional analysis and comparison to chemical transmission

  • T.B. Kepler

    The effect of electrical coupling on the frequency of model neuronal oscillators

    Science

    (1990)
  • A.A. Sharp

    Artificial electrical synapses in oscillatory networks

    J. Neurophysiol.

    (1992)
  • A. Sherman et al.

    Rhythmogenic effects of weak electrotonic coupling in neuronal models

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • Cited by (214)

    • In vivo models of cortical acquired epilepsy

      2016, Journal of Neuroscience Methods
    • A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro

      2015, Brain Research
      Citation Excerpt :

      However, seizure generation is likely to be multifactorial involving not only synaptic and intrinsic neuronal properties but also non-synaptic interactions (e.g. gap junction signaling, field effects and ion fluctuations). In vitro experiments have shown that targeting the latter mechanisms often leads to an effective blockade of epileptiform activity (Hochman, 2009; Jefferys, 1995; Velazquez and Carlen, 2000). Non-synaptic interactions thus appear to be an obvious focal point for developing new therapeutic strategies.

    View all citing articles on Scopus
    View full text