Sexually dimorphic long-term effects of an early life experience on AMPA receptor subunit expression in rat brain

Neonatal handling, an experimental model of early life experiences, is known to affect hypothalamic-pituitary-adrenal (HPA) axis function, thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. AMPA receptors (AMPARs) mediate fast synaptic transmission at excitatory glutamatergic synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPARs are composed of four types of subunits, designated as AMPA glutamate receptor subunits (GluA1, GluA2, GluA3 and GluA4), which combine to form tetramers. The present study addressed the question of whether neonatal handling (15min daily maternal separation from postnatal day 1 (PND1) to PND21) might have an effect on GluA1-4 mRNA levels in adult rat male and female brain using in situ hybridization. We have identified selective sexually dimorphic effects of neonatal handling on the mRNA expression levels of AMPAR subunits in adult rat hippocampus and nuclei of the amygdaloid complex. In the dorsal hippocampus GluA1 mRNA levels were increased in handled males, while they were decreased in handled female animals. In the ventral hippocampus and the amygdaloid complex GluA2 mRNA was lower in handled females, while no effect was observed in handled males. Furthermore, we observed that neonatal handling induced in both sexes decreases of GluA2 mRNA in the dorsal hippocampus, as well as in the somatosensory and occipital cortex, of GluA3 mRNA in most hippocampal areas, amygdaloid complex and cortical regions studied, and of GluA4 mRNA in the ventral hippocampus. These results show that glutamatergic transmission is markedly affected by an early experience. The neonatal handling-induced alterations in AMPAR subunit composition are in line with the increased brain plasticity, the more effective HPA axis function, and in general the more adaptive behavioral phenotype known to characterize the handled animals.