The Glutamine-Glutamate Cycle Contributes to Behavioral Feminization in Female Rats

Introduction: In perinatal female rats, the glutamine (Gln)- glutamate cycle (GGC) constitutively supplies Gln to neurons of the ventral lateral ventromedial nucleus of the hypothalamus (vlVMH) to sustain glutamatergic synaptic transmission (GST). In contrast, male pups may use Gln only during periods of elevated neuronal activity. Perinatal disruption of the GGC has sex-specific effects on the GST and morphology of vlVMH neurons during adulthood. Since (vl) VMH neuronal activities regulate mating behavior expression, we hypothesize that maintaining a perinatal intact GGC may be essential for the sexual differentiation of reproductive behaviors. Methods: Using perinatal rats of both sexes, we pharmacologically killed astrocytes or blocked the GGC and supplemented them with exogenous Gln. Mating behavior, an open-field test and protein levels of GGC enzymes were examined during adulthood. Results: Killing astrocytes reduced mating behavior expression by 38-48% and 71-72% in male and female rats, respectively. Any blocker targeting the GGC consistently reduced female lordosis behavior by 52-73% and increased glutaminase protein levels in the hypothalamus, but blockers had no effect on the expression of or motivation for copulatory behavior in males. Exogenous Gln supplementation partly rescued the decline in Gln synthetase inhibitor-mediated sex behavior in females. Perinatal interruption of the GGC did not increase induced expression of female sexual behavior in hormone-primed castrated male rats or affect locomotion or anxiety-like behavior in either sex. Conclusion: The intact GGC is necessary for behavioral feminization in female rats and may play little or no role in behavioral masculinization or defeminization in males.