Plasticity of both excitatory and inhibitory synapses is associated with seizures induced by removal of chronic blockade of activity in cultured hippocampus.

Published

Journal Article

One factor common to many neurological insults that can lead to acquired epilepsy is a loss of afferent neuronal input. Neuronal activity is one cellular mechanism implicated in transducing deafferentation into epileptogenesis. Therefore the effects of chronic activity blockade on seizure susceptibility and its underlying mechanisms were examined in organotypic hippocampal slice cultures treated chronically with the sodium channel blocker, tetrodotoxin (TTX), or the N-methyl-D-aspartate receptor (NMDAR) antagonist, D-2-amino-5-phosphonovaleric acid (D-APV). Granule cell field potential recordings in physiological buffer revealed spontaneous electrographic seizures in 83% of TTX-, 9% of D-APV-, but 0% of vehicle-treated cultures. TTX-induced seizures were not associated with membrane property alterations that would elicit granule cell hyperexcitability. Seizures were blocked by glutamate receptor antagonists, suggesting that plasticity in excitatory synaptic circuits contributed to seizures. The morphology of granule cells and their mossy fiber axons remained largely unchanged, and the number of synapses onto granule cells measured immunohistochemically was not increased in TTX- or D-APV-treated cultures. However, voltage-clamp recordings revealed that miniature excitatory postsynaptic current frequency and kinetics were increased and miniature inhibitory postsynaptic current kinetics were decreased in D-APV- and TTX-treated cultures compared with vehicle. Changes were more profound and qualitatively different in TTX- compared with D-APV-treated cultures, consistent with the dramatic effects of TTX treatment on seizure expression. We propose that chronic blockade of action potentials by TTX induces homeostatic responses including plasticity of both excitatory and inhibitory synapses. Removal of TTX unmasks the impact of these synaptic plasticities on local circuit excitability, resulting in spontaneous seizures.

Full Text

Duke Authors

Cited Authors

  • Bausch, SB; He, S; Petrova, Y; Wang, X-M; McNamara, JO

Published Date

  • October 2006

Published In

Volume / Issue

  • 96 / 4

Start / End Page

  • 2151 - 2167

PubMed ID

  • 16790597

Pubmed Central ID

  • 16790597

International Standard Serial Number (ISSN)

  • 0022-3077

Digital Object Identifier (DOI)

  • 10.1152/jn.00355.2006

Language

  • eng

Conference Location

  • United States