Impaired synaptogenesis and long-term modulation of behavior following postnatal elevation of GABA levels in mice.
Antiepileptic drugs acting through the potentiation of GABAergic pathways have adverse effects on brain development. Increased risk of impaired intellectual development has been reported in children born to women treated for epilepsy during pregnancy. We have previously shown, in mice, that treatment with the antiepileptic drug vigabatrin (GVG) on postnatal days 4-14 delays reflex development in the newborn and impairs learning and memory in the adult. Here, we report the time course in which postnatal GVG treatment induced behavioral changes in an open field test and had a detrimental developmental effect on recognition memory in mice. Furthermore, GVG treatment significantly modulated the expression of synaptobrevin/vesicle-associated membrane protein (VAMP) II and synaptotagmin (Synt) I. A short-term decrease in the expression of these proteins was followed by a long-term elevation in their expression in both the hippocampus and the cerebral cortex. In contrast, no changes were detected in the levels of Synt II or in the vesicular GABA transporter. The over-expression of VAMP II and Synt I in the GVG-treated mice was associated with a significant decrease in the basal field excitatory postsynaptic potentials (fEPSP) and modulated the response to repeated stimulation. The changes observed in synaptogenesis may explain the behavioral impairment induced by postnatal GVG treatment and may suggest a possible mechanism for the detrimental effect of antiepileptic drugs acting through elevation of GABA levels.
Department of Developmental Molecular Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Tamar
T
Levav
Orly
O
Wirthaim
Reut
R
Weiss
Yoram
Y
Grossman
Hava
H
Golan
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D049029:Dystrophin-Associated Proteins / Q000096:biosynthesis; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D050988:Vesicle-Associated Membrane Protein 2 / Q000096:biosynthesis; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000096:biosynthesis; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D049029:Dystrophin-Associated Proteins; D050988:Vesicle-Associated Membrane Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C091824:syntrophin; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin