Hippocampal synaptic plasticity, memory, and epilepsy: effects of long-term valproic acid treatment.
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.
Sgobio
Carmelo
C
Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Ghiglieri
Veronica
V
Costa
Cinzia
C
Bagetta
Vincenza
V
Siliquini
Sabrina
S
Barone
Ilaria
I
Di Filippo
Massimiliano
M
Gardoni
Fabrizio
F
Gundelfinger
Eckart D
ED
Di Luca
Monica
M
Picconi
Barbara
B
Calabresi
Paolo
P
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology; D001522:Behavior, Animal; D001703:Biophysics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation / Q000379:methods; D004827:Epilepsy / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D005518:Food Preferences / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051528:Guanylate Kinases; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D017966:Pyramidal Cells / Q000473:pathology / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism; D012919:Social Behavior; D014635:Valproic Acid / Q000009:adverse effects* / Q000494:pharmacology
D000927:Anticonvulsants; C498441:Bsn protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; D014635:Valproic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051528:Guanylate Kinases