Stress in critical period of early life influences glutamate excitatory neurotransmission: implication for neuropsychiatric disorders

Early adverse events occurring during critical periods of brain development may shape the individual’s developmental trajectory and increase vulnerability to stress-related disorders across lifespan. The aim of my PhD thesis was to investigate the role of glutamatergic neurotransmission in the early-life stress induced impairments of emotional, cognitive, and social scaffolding in functionally involved brain regions. The study was realized by using the model of postweaning social isolation (PWSI) in mice and the model of perinatal stress (PRS) in rat. Firstly, I compared the behavioral and biochemical profiles of PWSI-induced inbred C57BL/6 N mice to those of BTBR mice, a rodent model used to study autism spectrum disorders in humans. Male C57BL/6 N mice were socially housed at weaning (postnatal day 21) or isolated for four weeks before being subjected to experimental analysis at 48 days of age. Male BTBR mice were socially housed at weaning and subjected to analysis at the same age. Metabotropic glutamate receptor of type 2 (mGluR2), glucocorticoid and mineralocorticoid receptors levels were all decreased in the hippocampus of PWSI and BTBR animals. Moreover, both PWSI mice and BTBR mice displayed decreased social behavior (social investigation and ultrasonic vocalizations), demonstrating that the lack of social stimuli throughout adolescence causes an endophenotype that mirrors some behavioral features of autism spectrum disorders. Secondly, I investigated the possible corrective role exerted by resocialization on the PWSI-induced hippocampal glutamatergic disequilibrium. Results showed that PWSI-induced reduction of hippocampal mGluR2 was not recovered by one week of resocialization. I have also investigated the effect of PRS in adult and aged rats of both sexes on the expression of AMPA and GABAA receptor subunits in the hippocampus (ventral and dorsal) and prefrontal cortex in relation to emotional and cognitive behaviors. PRS induced sex-dimorphic and age-dependent effects on some receptor subunits and behavior. Particularly, in both adulthood and ageing, PRS reduced open-arm exploration and recognition score in males, while it improved them in females. Interestingly, in the dorsal hippocampus, PRS reduced the expression of the GluA2 subunit in adult male rats and increased the expression in adult female rats. Moreover, PRS reduced the expression of the GluA3 AMPA receptor subunit in the prefrontal cortex and in dorsal hippocampus of adult male rats, an effect which was limited to the prefrontal cortex of adult female rats. Remarkably, changes in GluA2/GluA3 subunits and behavior induced by PRS persisted in aged male rats, but not females. The α1 subunit of the pentameric GABAA receptor was also studied in adult and aged rats of both sexes. PRS enhanced the expression of the α1 subunit of GABAA in the dorsal hippocampus of both sexes and reduced it in the prefrontal cortex exclusively in females. In aged PRS subjects a reduction of GABAA-α1 subunit protein levels in the prefrontal cortex was observed in the male gender. Extending the analysis to synaptic vesicle proteins we found reduction of synaptophysin, syntaxin and rab3a levels in the ventral hippocampus of PRS males, but not females, at adulthood and ageing. Interestingly, control male rats are characterized by a greater density of hippocampal levels of syntaxin, munc-18, synapsin IIa, VAMP, synaptophysin and rab3a with respect to female rats. This difference was abolished by PRS, suggesting that PRS caused dysmasculinization across lifespan. These findings suggest that changes in the expression levels of AMPA and GABAA receptors contribute to the sex-divergent behavioral phenotype induced by PRS in adult and aged rats. Collectively, my research shows that early-life stress-induced alterations converge to severe impairment of glutamatergic neurotransmission, underscoring its key role in determining and maintaining the proper developmental trajectory across the lifespan.