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.

Distinct expression and distribution of vesicular proteins in the hippocampus of TNFa-deficient mice during development.

Tumor necrosis factor alpha (TNFa) is a cytokine produced mainly by cells of the immune system. It is also expressed by brain neurons and glia. In the brain, TNFa governs synaptic plasticity, such as long-term potentiation and learning. Using TNFa-deficient mice (TNFa-KO) and immunohistochemical techniques, we resolved the spatio-temporal effect of TNFa on the expression of vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (v-SNARE) in the presynaptic terminals of the hippocampus during the first month of development. During postnatal days 1-14, the levels of Synaptotagmin I and VAMP II were similar in the hippocampus of TNFa-KO and wild type (wt) mice. However, the levels of Syntaptotagmin II were reduced in the pyramidal cell layer of the CA1 region in TNFa-KO. At postnatal day 21, both proteins accomplished comparable levels in the hippocampus of TNFa-KO and wt mice. In addition, TNFa deficiency impairs the correlation of expression of Synaptotagmin I and II in CA1 region. The expression of those proteins in the CA1 stratum radiatum was uniform during development and similar in both mice groups. Higher expression of all examined proteins was demonstrated in dendritic fields of the CA3 region in TNFa-KO as compared to wt mice. We suggest that the impairment of synaptic plasticity by TNFa may be related to its modulation of synaptic vesicle proteins.