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

• Published in: Biological psychiatry (1969) Vol. 67; no. 6; pp. 567 - 574
• Main Authors: Sgobio, Carmelo, Ghiglieri, Veronica, Costa, Cinzia, Bagetta, Vincenza, Siliquini, Sabrina, Barone, Ilaria, Di Filippo, Massimiliano, Gardoni, Fabrizio, Gundelfinger, Eckart D., Di Luca, Monica, Picconi, Barbara, Calabresi, Paolo
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.03.2010; Elsevier
• Subjects: Animals; Anticonvulsants - adverse effects; Anticonvulsants - pharmacology; Antiepileptic drugs; Behavior, Animal; Biological and medical sciences; Biophysics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; dendrite branching; Disease Models, Animal; Disks Large Homolog 4 Protein; Electric Stimulation - methods; electrophysiology; Epilepsy - complications; Epilepsy - drug therapy; Epilepsy - genetics; epileptic seizures; Food Preferences - physiology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Guanylate Kinases; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; hippocampal nonspatial learning; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; In Vitro Techniques; Intracellular Signaling Peptides and Proteins - metabolism; long-term potentiation; Medical sciences; Membrane Proteins - metabolism; Memory Disorders - etiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - deficiency; Nervous system (semeiology, syndromes); Neurology; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neuropharmacology; Pharmacology. Drug treatments; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Pyramidal Cells - pathology; Pyramidal Cells - physiology; Receptors, Glutamate - metabolism; Social Behavior; Valproic Acid - adverse effects; Valproic Acid - pharmacology; hippocampal nonspatial learning; electrophysiology; dendrite branching; Antiepileptic drugs; epileptic seizures; long-term potentiation; Psychotropic; Epilepsy; Memory; Central nervous system; Electrophysiology; Long term potentiation; Anticonvulsant; Encephalon; Learning; Acquisition process; Mood stabilizer; Synaptic plasticity; Neurological disorder; Nervous system diseases; 4-Aminobutyrate transaminase; Enzyme; Transferases; Enzyme inhibitor; Valproic acid; Long term; Cerebral disorder; Dendrite; Histone deacetylase inhibitor; Treatment; Convulsion; Transaminases; Central nervous system disease; Hippocampus
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2009.11.008

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). 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. 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. 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.