Chronic Postnatal Chemogenetic Activation of Forebrain Excitatory Neurons Modulates Astrocyte-Associated Function and Metabolism in Adult Male Mice.

Early adversity increases vulnerability for adult psychopathology. Across multiple preclinical models of early adversity, there are reports of astrocyte 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 astrocyte function in adulthood. Our results show that postnatal hM3Dq-mediated chemogenetic activation of CaMKIIα-positive forebrain excitatory neurons not only increases anxiety-like behavior but also evokes bidirectional transcriptional regulation of multiple astrocyte-associated genes in the neocortex and hippocampi. While Gfap, Aldh1l1, Eaat1, 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. Chronic postnatal chemogenetic activation of CaMKIIα-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 hippocampus in adulthood in animals with a history of postnatal chemogenetic activation of forebrain excitatory neurons. Our findings indicate that chemogenetically driving Gq signaling chronically during the postnatal window in forebrain excitatory neurons results in persistent changes well into adulthood, with enhanced anxiety-like behaviors and disrupted astrocyte function and metabolism, phenocopying specific changes in astrocyte function noted following early adversity.