TY - JOUR
T1 - Hippocampal Synaptic Plasticity, Memory, and Epilepsy
T2 - Effects of Long-Term Valproic Acid Treatment
AU - Sgobio, Carmelo
AU - Ghiglieri, Veronica
AU - Costa, Cinzia
AU - Bagetta, Vincenza
AU - Siliquini, Sabrina
AU - Barone, Ilaria
AU - Di Filippo, Massimiliano
AU - Gardoni, Fabrizio
AU - Gundelfinger, Eckart D.
AU - Di Luca, Monica
AU - Picconi, Barbara
AU - Calabresi, Paolo
PY - 2010/3/15
Y1 - 2010/3/15
N2 - 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.
AB - 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.
KW - Antiepileptic drugs
KW - dendrite branching
KW - electrophysiology
KW - epileptic seizures
KW - hippocampal nonspatial learning
KW - long-term potentiation
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UR - http://www.scopus.com/inward/citedby.url?scp=76849114494&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2009.11.008
DO - 10.1016/j.biopsych.2009.11.008
M3 - Article
C2 - 20074705
AN - SCOPUS:76849114494
VL - 67
SP - 567
EP - 574
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 6
ER -