Perinatal blockade of neuronal glutamine transport sex‐differentially alters glutamatergic synaptic transmission and organization of neurons in the ventrolateral ventral media hypothalamus of adult rats

Compared to male pups, perinatal female rats rely heavily on neuronal glutamine (Gln) transport for sustaining glutamatergic synaptic release in neurons of the ventrolateral ventral media nucleus of the hypothalamus (vlVMH). VMH mainly regulates female sexual behavior and increases glutamate release of perinatal hypothalamic neurons, permanently enhances dendrite spine numbers and is associated with brain and behavioral defeminization. We hypothesized that perinatal interruption of neuronal Gln transport may alter the glutamatergic synaptic transmission during adulthood. Perinatal rats of both sexes received an intracerebroventricular injection of a neuronal Gln uptake blocker, alpha‐(methylamino) isobutyric acid (MeAIB, 5 mM), and were raised until adulthood. Whole‐cell voltage‐clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) and evoked EPSCs (eEPSCs) of vlVMH neurons in adult rats with the perinatal pretreatment were conducted and neuron morphology was subjected to post hoc examination. Perinatal MeAIB treatment sex‐differentially increased mEPSC frequency in males, but decreased mEPSC amplitude and synaptic Glu release in females. The pretreatment sex‐differentially decreased eEPSC amplitude in males but increased AMPA/NMDA current ratio in females, and changed the morphology of vlVMH neurons of adult rats to that of the opposite sex. Most alterations in the glutamatergic synaptic transmission resembled the changes occurring during MeAIB acute exposure in perinatal rats of both sexes. We conclude that perinatal blockade of neuronal Gln transport mediates changes via different presynaptic and postsynaptic mechanisms to induce sex‐differential alterations of the glutamatergic synaptic transmission and organization of vlVMH neurons in adult rats. These changes may be permanent and associated with brain and behavior feminization and/or defeminization in rats. A schematic representation of sex‐differential alterations of glutamatergic synaptic transmission of neurons in the ventral lateral ventromedial nucleus of the hypothalamus (vlVMH) of male and female adult rats at ages between postnatal day (PN) 60 and PN103. The animals were centrally injected with a neuronal glutamine (Gln) uptake blocker, MeAIB, on PN 5 or 6. Note the sex differences in the presynaptic and postsynaptic mechanisms and neuronal morphology mediated by perinatal MeAIB administration. Most of the changes may be permanent.