Chronic postnatal chemogenetic activation of forebrain excitatory neurons modulates adult glial function and metabolism in male mice

Early adversity increases vulnerability for adult psychopathology. Across multiple pre-clinical models of early adversity, there are reports of glial dysfunction and disrupted amino acid neurotransmission, along with maladaptive behavioral responses in adulthood. Disrupted G-protein coupled receptor signaling is known to phenocopy specific consequences of early life adversity. Enhanced Gq signaling in the forebrain excitatory neurons in early postnatal life programs anxio-depressive behaviors in adulthood, accompanied by altered neuronal glutamate and GABA metabolism in mouse models. We hypothesized that enhancing Gq signaling in forebrain excitatory neurons in early postnatal life may also impact glial function in adulthood. Our results show that postnatal hM3Dq-mediated chemogenetic activation of CaMKII-positive forebrain excitatory neurons not only increases anxiety-like behavior, but also evokes bidirectional transcriptional regulation of multiple glia-associated genes in the neocortex and hippocampi. While Gfap, Aldh1l1, S100{beta}, Eaat1, Eaat2 and Eaat3, mRNA levels were reduced in the neocortex, they were enhanced in the hippocampus, and a similar pattern was noted for GFAP protein levels. Transient, postnatal chemogenetic activation of CaMKII-positive neurons did not alter astrocyte cell density in both the neocortex and the hippocampus. Using (1H-(13C)) NMR spectroscopy, we observed a significant decline in astrocyte-specific glutamate and GABA neurotransmitter turnover, and a reduction in astrocyte metabolic flux within the neocortex and the hippocampus in adulthood in animals with a history of postnatal chemogenetic activation of forebrain excitatory neurons. Our findings indicate that chemogenetically driving Gq signaling transiently during the postnatal window in forebrain excitatory neurons results in persistent changes well into adulthood, with enhanced anxiety-like behaviors and disrupted glial function and metabolism, phenocopying specific changes in glial function noted following early adversity.