Cellular and molecular basis for stress-induced depression

TLDR

Chronic stress contributes to psychiatric disorders by disrupting medial prefrontal cortex function. The study aims to uncover the molecular and cellular determinants in the mPFC that underlie stress‑induced depression. p11 is concentrated in dopamine D2‑receptor‑expressing glutamatergic neurons of layer II/III in the prelimbic cortex. Chronic restraint stress selectively reduces p11 in these neurons, producing depression‑like behaviors that are reversed by SSRIs and TCAs, and viral restoration of p11 in D2+ PrL glutamatergic neurons rescues these behaviors by restoring glutamatergic transmission, establishing p11 as a key regulator of stress‑induced depression.

Abstract

Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.