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

Network dysfunction is implicated in numerous diseases and psychiatric disorders, and the hippocampus serves as a common origin for these abnormalities. To test the hypothesis that chronic modulation of neurons and astrocytes induces impairments in cognition, we activated the hM3D(Gq) pathway in CaMKII+ neurons or GFAP+ astrocytes within the ventral hippocampus across 3, 6, and 9 months. CaMKII-hM3Dq activation impaired fear extinction at 3 months and acquisition at 9 months. Both CaMKII-hM3Dq manipulation and aging had differential effects on anxiety and social interaction. GFAP-hM3Dq activation impacted fear memory at 6 and 9 months. GFAP-hM3Dq activation impacted anxiety in the open field only at the earliest time point. CaMKII-hM3Dq activation modified the number of microglia, while GFAP-hM3Dq activation impacted microglial morphological characteristics, but neither affected these measures in astrocytes. Overall, our study elucidates how distinct cell types can modify behavior through network dysfunction, while adding a more direct role for glia in modulating behavior.