Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain

Whereas adult sex differences in brain morphology and behavior result from developmental exposure to steroid hormones, the mechanism by which steroids differentiate the brain is unknown. Studies to date have described subtle sex differences in levels of proteins and neurotransmitters during brain de velopment, but these have lacked explanatory power for the profound sex dif ferences induced by steroids. We report here a major divergence in the resp onse to injection of the gamma -aminobutyric acid type A (GABA(A)) agonist, muscimol, in newborn male and female rats. In females, muscimol treatment primarily decreased the phosphorylation of cAMP response element binding pr otein (CREB) within the hypothalamus and the CA1 region of the hippocampus. In contrast, muscimol increased the phosphorylation of CREB in males withi n these same brain regions. Within the arcuate nucleus, muscimol treatment increased the phosphorylation of CREB in both females and males. Thus, the response to GABA can be excitatory or inhibitory on signal-transduction pat hways that alter CREB phosphorylation depending on the sex and the region i n developing brain. This divergence in response to GABA allows for a previo usly unknown form of steroid-mediated neuronal plasticity and may be an ini tial step in establishing sexually dimorphic signal-transduction pathways i n developing brain.