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1 Dept. of Pharmacology, Rm C2007, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, Maryland, 20814, United States; Prog. in Neuroscience, Uniformed Services University, Bethesda, Maryland, United States
2 Prog. in Neuroscience, Uniformed Services University, Bethesda, Maryland, United States
3 Dept. of Pharmacology, Rm C2007, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, Maryland, 20814, United States
4 Dept. of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina, United States; Dept. of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States; Dept. of Pharmacology and Molecular Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: sbausch{at}usuhs.mil.
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-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 epilepsy was 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 mEPSC frequency and kinetics were increased and mIPSC kinetics were decreased in D-APV- and TTX-treated cultures compared to vehicle. Changes were more profound and qualitatively different in TTX- compared to 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.
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