biostudies-literatureLiu ZJSTI2030-Major ProjectScience and Technology Program of GuangzhouNational Natural Science Foundation of ChinaScience and Technology Development Plan of Jilin provincee12170https://www.ebi.ac.uk/biostudies/studies/S-EPMC12915128biostudies-literatureUnknown13(10)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 theAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Adenylyl Cyclase 8 in Dorsal CA1 Neurons Prevents Depressive-Like Behaviors by Maintaining Neuronal Excitability and Glutamatergic Neurotransmission Through TIP39-PTH2R Signaling.PMC129151282025A04J3796824715392022ZD02143003220082420250102276JCTian MQiang BYZha HWChen WBZhu XJChen ZYSun SSBi JRWei RLiu ZJYu ZYSun DZhang YQWang MMWang HJfalseAdenylyl 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 the2026-01-01T00:00:00Z2026 Feb2026-07-16T06:32:56.379Z2026-07-09T10:39:46.17ZS-EPMC129151284138717010.1002/advs.202512170