Tumor necrosis factor alpha (TNFalpha) is a cytokine produced mainly by cells of the immune system. It is also expressed by brain neurons and glia. The physiological role of TNFalpha in the brain is not yet fully clear. Using TNFalpha-deficient mice, we have examined its role in hippocampal development and function. We report here that TNFalpha is involved in the regulation of morphological development in the hippocampus. TNFalpha-deficient mice exhibited an accelerated maturation of the dentate gyrus region and smaller dendritic trees in CA1 and CA3 regions in young mouse. In addition to its involvement in hippocampal morphogenesis, TNFalpha deficiency specifically improved performance of affected mice in behavioral tasks related to spatial memory. Moreover, lack of TNFalpha increased the expression of nerve growth factor (NGF), but not brain-derived neurotrophic factor (BDNF), following performance of the learning task. Our results suggest that TNFalpha actively influences hippocampal development and function. In adult mice, TNFalpha may interfere with memory consolidation, perhaps by regulating NGF levels.

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-ethylmaleimidesensitive 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.

Antiepileptic drugs acting through the potentiation of GABA-ergic pathways have harmful effects on brain development. Increased risk of impaired intellectual development was reported in children born to women treated for epilepsy during pregnancy. Here we examined the vulnerability of the developing brain to treatment with one of the new antiepileptic drugs--vigabatrin--during two time periods in newborn mice (postnatal days 1-7 and 4-14) which parallel the third trimester of human embryo brain development. Delayed development of sensory and motor reflexes, reduced mobility in the open field, impaired object recognition and deficient spatial learning and memory were observed independently of the treatment period. On the contrary, specific susceptibility to the age of exposure was detected in various motor functions. A number of morphological correlates may explain these behavioral alterations; a transient increase in CA1 pyramidal cell layer (P < 0.001) and decrease in granular cell layer (P < 0.05) in hippocampus were detected at postnatal day 7. In addition, a significantly lower cell density was observed in the adult mouse brain in all layers of the M2 cerebral cortex of mice treated during days 4-14, compared to the controls (P < 0.05). Our findings demonstrated short- and long-term deleterious effects of vigabatrin treatment and suggest a specific vulnerability of the developing motor system to GABA enhancement during the first postnatal week.

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