Adenylyl Cyclase 8 in Dorsal CA1 Neurons Prevents Depressive‐Like Behaviors by Maintaining Neuronal Excitability and Glutamatergic Neurotransmission Through TIP39‐PTH2R Signaling

Depression, a common neuropsychiatric disorder, profoundly disrupts individuals' daily lives. Although the pathogenesis of depression is intensively investigated for decades, its underlying mechanisms remain elusive. Here, dysfunctional adenylyl cyclase 8 (Adcy8) is identified as a critical risk factor for the development of depression. Adcy8 expression is selectively decreased in the hippocampus, but not in the cortex, thalamus, and hypothalamus, of mice exposed to chronic stress. Adcy8 conditional knockout (CKO) in excitatory neurons, particularly dorsal CA1 (dCA1) neurons, resulted in pronounced depressive-like behaviors. Depletion of Adcy8 in dCA1 neurons reduces neuronal excitability and glutamatergic neurotransmission. Further mechanistic studies reveal a remarkable inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway by Adcy8 CKO, which downregulates parathyroid hormone 2 receptor (PTH2R) level in the hippocampus. Knocking down Pth2r with AAV-shRNA duplicates the impairments in neuronal excitability, glutamatergic neurotransmission and depressive-like behaviors. In contrast, overexpression of PTH2R in Adcy8 CKO hippocampus rescues these deficits. Chronic infusion of TIP39, the endogenous ligand for PTH2R, into the hippocampus also alleviates depressive-like behaviors of Adcy8 CKO mice. Taken together, these results uncover critical roles of Adcy8 in suppressing depressive-like behaviors, likely by maintaining the excitability and glutamatergic neurotransmission of dCA1 neurons through TIP39-PTH2R signaling pathway.