The glutamine‐glutamate cycle regulates synaptic glutamate release in the ventrolateral ventromedial nucleus of the hypothalamus of perinatal female rats

The astrocytic glutamine (Gln)‐glutamate (Glu) cycle ( GGC ) supplies Gln for the regulation of glutamatergic synaptic transmission ( GST ) in the adult hippocampus. Increased synaptic Glu release in the perinatal ventrolateral ventromedial nucleus of the hypothalamus (vl VMH ) modulates sexual differentiation, however, whether GGC regulates GST in the perinatal vl VMH has not been determined. Sex differences in oestradiol (E 2 ) levels exist in the neonatal hypothalamus, and E 2 increases levels of glutamine synthetase and glutaminase, two key enzymes involved in the GGC . Thus, it is hypothesised that sexually dimorphic phenotypes may exist in glutamatergic synapses associated with the GGC in the vl VMH in perinatal rats. Whole‐cell voltage‐clamp recordings in vl VMH neurones in brain slices from male and female pups revealed that pharmacological disruption of the GGC by α‐(methylamino) isobutyric acid (5 mmol L ‐1 ), which blocks neuronal Gln uptake; or by l ‐methionine sulphoximine (1.5 mmol L ‐1 ), which inhibits astrocytic Gln synthesis, decreased miniature excitatory postsynaptic current ( mEPSC ) amplitudes in female but not male pups. By contrast, GGC interruptions decreased evoked (e) EPSC amplitudes in both sexes following increased synaptic activity produced by a period of stimulation. In male pups, the decreased eEPSC s were attributable to reduced Glu release, as assessed by paired‐pulse stimulations, whereas, in female pups, they were attributable to decreased Glu content in the synaptic vesicles, as measured by strontium‐evoked mEPSC s. The l ‐methionine sulphoximine‐mediated decrease in eEPSC s was rapidly rescued by exogenous Gln in female but not male pups. The reductions in mEPSC s and eEPSC s in female pups were accompanied by enhanced blocking effects of the low‐affinity Glu AMPA receptor antagonist, γ‐ d ‐glutamylglycine, consistent with diminished Glu release. In conclusion, female, but not male pups, rely on constitutive astrocytic Gln for sustained synaptic Glu release in the vl VMH . This glutamatergic synaptic phenotype may be associated with brain and behaviour feminisation and/or defeminisation in rats.