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Although the pathogenesis of depression is intensively investigated for decades, its underlying mechanisms remain elusive. Here, dysfunctional adenylyl cyclase 8 (\n                    <jats:italic>Adcy8<\/jats:italic>\n                    ) is identified as a critical risk factor for the development of depression.\n                    <jats:italic>Adcy8<\/jats:italic>\n                    expression is selectively decreased in the hippocampus, but not in the cortex, thalamus, and hypothalamus, of mice exposed to chronic stress.\n                    <jats:italic>Adcy8<\/jats:italic>\n                    conditional knockout (CKO) in excitatory neurons, particularly dorsal CA1 (dCA1) neurons, resulted in pronounced depressive\u2010like behaviors. Depletion of\n                    <jats:italic>Adcy8<\/jats:italic>\n                    in dCA1 neurons reduces neuronal excitability and glutamatergic neurotransmission. Further mechanistic studies reveal a remarkable inhibition of the mitogen\u2010activated protein kinase (MAPK) signaling pathway by\n                    <jats:italic>Adcy8<\/jats:italic>\n                    CKO, which downregulates parathyroid hormone 2 receptor (PTH2R) level in the hippocampus. Knocking down\n                    <jats:italic>Pth2r<\/jats:italic>\n                    with AAV\u2010shRNA duplicates the impairments in neuronal excitability, glutamatergic neurotransmission and depressive\u2010like behaviors. In contrast, overexpression of PTH2R in\n                    <jats:italic>Adcy8<\/jats:italic>\n                    CKO hippocampus rescues these deficits. Chronic infusion of TIP39, the endogenous ligand for PTH2R, into the hippocampus also alleviates depressive\u2010like behaviors of\n                    <jats:italic>Adcy8<\/jats:italic>\n                    CKO mice. Taken together, these results uncover critical roles of\n                    <jats:italic>Adcy8<\/jats:italic>\n                    in suppressing depressive\u2010like behaviors, likely by maintaining the excitability and glutamatergic neurotransmission of dCA1 neurons through TIP39\u2010PTH2R signaling pathway.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512170","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T02:01:16Z","timestamp":1765591276000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenylyl Cyclase 8 in Dorsal CA1 Neurons Prevents Depressive\u2010Like Behaviors by Maintaining Neuronal Excitability and Glutamatergic Neurotransmission Through TIP39\u2010PTH2R Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Zi\u2010Jie","family":"Liu","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine School of 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