Trends in Neurosciences
ReviewGap junctions, synchrony and seizures
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.
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2015, Brain ResearchCitation 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.