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

## TL;DR

This study shows that adenylyl cyclase 8 in hippocampal neurons prevents depression-like behaviors by supporting neuronal function through a specific signaling pathway.

## Contribution

The study identifies Adcy8 as a novel factor in depression and reveals the TIP39-PTH2R signaling pathway's role in maintaining neuronal function.

## Key findings

- Adcy8 depletion in dCA1 neurons causes depressive-like behaviors and reduces neuronal excitability.
- Adcy8 regulates glutamatergic neurotransmission via the MAPK pathway and PTH2R levels.
- TIP39 infusion or PTH2R overexpression rescues depressive-like behaviors in Adcy8-deficient mice.

## Abstract

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.

Depression, a prevalent neuropsychiatric disorder with unclear pathogenesis, involves dysfunctional adenylyl cyclase 8 (Adcy8) as a key risk factor. Chronic stress selectively reduces Adcy8 expression in the dorsal CA1 (dCA1) neurons. Depletion of Adcy8 in dCA1 excitatory neurons induces depressive‐like behaviors by impairing neuronal excitability and glutamatergic neurotransmission, which is mediated by inhibiting MAPK signaling and decreasing PTH2R levels.