Chronic Gq activation of ventral hippocampal neurons and astrocytes differentially affects memory and behavior

Network dysfunction has been implicated in numerous diseases and psychiatric disorders, and the hippocampus serves as a common origin for these abnormalities. In this study, we tested the hypothesis that chronic induction of local changes in neurons and astrocytes is sufficient to induce impairments in cognition and behavior. We chronically activated the hM3D(Gq) pathway in CaMKII+ neurons or GFAP+ astrocytes within the ventral hippocampus across 3, 6 and 9 months. We observed that CaMKII-hM3Dq activation impaired fear acquisition, decreased anxiety and social interaction, and modified spatial odor memory and novel environment exploration, while GFAP-hM3Dq activation impaired fear acquisition and enhanced recall. CaMKII-hM3Dq activation modified the number of microglia, while GFAP-hM3Dq activation impacted microglial morphological characteristics, but neither affected astrocytes. Manipulation of both cell types increased the presence of phosphorylated tau at the earliest time point. Overall, our study provides evidence for how each of these cell types are uniquely engaged in disorders that have characteristic network dysfunction while adding a more direct role for glia in modulating behavior. Main Points Behaviorally, neuronal Gq activation modified fear, anxiety, social and exploration behaviors, while astrocytic Gq activation induced changes in fear acquisition and recall. Cellularly, CaMKII-Gq activation modified microglial number, while GFAP-Gq activation affected microglial morphology. Neither cell manipulation affected astrocytic number or morphology. pTau is increased in vHPC at the 3 month time point for both neuronal and astrocytic Gq activation.