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Compensatory network alterations upon onset of epilepsy in synapsin triple knock-out mice.

Abstract：

:Adult synapsin triple-knockout mice exhibit epilepsy that manifests as generalized tonic-clonic seizures. Because in vitro recordings have shown a reduction in quantal release from inhibitory neurons, an inherent excitation-inhibition imbalance has been hypothesized as the direct culprit for epilepsy in these mice. We critically assessed this hypothesis by examining neurotransmission during the emergence of epilepsy. Using long-term video and telemetric EEG monitoring we found that synapsin triple-knockout mice exhibit an abrupt transition during early adulthood from a seizure-free presymptomatic latent state to a consistent symptomatic state of sensory-induced seizures. Electrophysiological recordings showed that during the latent period larger field responses could be elicited in slices from mutant mice. However, only after the transition to a symptomatic state in the adult mice did evoked epileptiform activity become prevalent. This state was characterized by resistance to the epileptiform-promoting effects of 4-aminopyridine, by marked hypersensitivity to blockage of GABAA receptors, and by the emergence of unresponsiveness to NMDA receptor antagonism, all of which were not observed during the latent period. Importantly, enhancement in inhibitory transmission was associated with upregulation of GAD67 expression without affecting the number of inhibitory neurons in the same brain areas where epileptiform activity was recorded. We therefore suggest that while deletion of the synapsins initially increases cortical network activity, this enhanced excitability is insufficient to elicit seizures. Rather, compensatory epileptogenic mechanisms are activated during the latent period that lead to an additional almost-balanced enhancement of both the excitatory and inhibitory components of the network, finally culminating in the emergence of epilepsy.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Ketzef M,Kahn J,Weissberg I,Becker AJ,Friedman A,Gitler D

doi

10.1016/j.neuroscience.2011.05.030

subject

Has Abstract

pub_date

2011-08-25 00:00:00

pages

108-22

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(11)00579-3

journal_volume

189

pub_type

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Compensatory network alterations upon onset of epilepsy in synapsin triple knock-out mice.