Hippocampal Synaptic Plasticity, Memory, and Epilepsy: Effects of Long-Term Valproic Acid Treatment

Carmelo Sgobio, Veronica Ghiglieri, Cinzia Costa, Vincenza Bagetta, Sabrina Siliquini, Ilaria Barone, Massimiliano Di Filippo, Fabrizio Gardoni, Eckart D. Gundelfinger, Monica Di Luca, Barbara Picconi, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Memory impairment is commonly associated with epilepsy, and the use of antiepileptic drugs (AEDs) causes additional neuropsychologic deficits that are of particular concern in learning-age children and elderly patients. The aim of this study was to investigate hippocampal synaptic plasticity and morphology as well as hippocampal-dependent memory in physiologic conditions and in a genetic model of epilepsy following chronic treatment with the widely used AED valproic acid (VPA). Methods: Mice lacking the presynaptic scaffolding protein Bassoon were used as a model of epilepsy. Electrophysiologic recordings were used to analyze basal glutamatergic synaptic transmission, paired-pulse facilitation, and activity-dependent long-term potentiation (LTP) in the CA1 area. Dendritic morphology and spine density were analyzed, and glutamate-related signaling was investigated by Western blot analysis. Social transmission of food preference test was used to investigate nonspatial hippocampal memory. Results: VPA treatment significantly reduced seizures frequency and mortality in epileptic mice. Long-term potentiation was absent at CA1 synapses of untreated epileptic mutant mice that also showed significant dendritic abnormalities. Treatment with VPA rescued physiologic LTP but did not reverse morphological abnormalities and deficits in nonspatial hippocampal memory observed in mutant epileptic mice. Moreover, VPA was found to induce per se dendritic abnormalities and memory dysfunction in normal animals. Conclusions: The impairment of hippocampal synaptic plasticity in epileptic mice, rescued by VPA treatment, might represent the mechanism underlying epilepsy-induced memory deficits. Moreover, the demonstration that VPA induces morphologic alterations and impairment in specific hippocampal-dependent memory task might explain the detrimental effects of antiepileptic treatment on cognition in human subjects.

Original languageEnglish
Pages (from-to)567-574
Number of pages8
JournalBiological Psychiatry
Volume67
Issue number6
DOIs
Publication statusPublished - Mar 15 2010

Keywords

  • Antiepileptic drugs
  • dendrite branching
  • electrophysiology
  • epileptic seizures
  • hippocampal nonspatial learning
  • long-term potentiation

ASJC Scopus subject areas

  • Biological Psychiatry

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