Sex-specific effects of in utero manipulation of GABA(A) receptors on pre- and postnatal expression of BDNF in rats.

Exposure to diazepam (DZ) during the last week of in utero development in rats induces neurobehavioral effects that do not become apparent in exposed animals until young adult ages. Some of the effects are sex specific. This study evaluated the hypothesis that late gestational exposure to DZ, a positive modulator of GABA(A) receptors, affects the developmental appearance of brain-derived neurotrophic factor (BDNF), an effect that could be linked to the later consequences of the exposure. Pregnant Long-Evans rats were injected with DZ (2.5 mg/kg) over gestation days 14-20, and their male and female offspring were evaluated for levels of BDNF mRNA and protein in the cerebral cortex and hypothalamus at fetal day 20 and at postnatal ages spanning birth to young adulthood. The effects of the exposure were sex and region specific. At fetal day 20 the expression of BDNF was reduced by about 20% in the hypothalamus of males only. The early exposure affected postnatal expression of BDNF in the hypothalamus only modestly, influencing the age-related profile in both sexes. Postnatal development of BDNF in the cerebral cortex was significantly affected by the in utero exposure in males only with mRNA levels lower in the exposed group and protein levels higher during juvenile ages. At adulthood, both levels were lower in DZ-exposed males. GABA serves a role as a trophic factor during early development, and these results suggest that manipulation of GABA(A) receptors during early development could interact with the developmental action of other trophic factors thereby leading to altered neural organization and later neurobehavioral dysfunction.