Long noncoding RNA Gm2694 drives depressive-like behaviors in male mice by interacting with GRP78 to disrupt endoplasmic reticulum homeostasis

Abstract

Long noncoding RNAs (lncRNAs) are involved in various biological processes and implicated in the regulation of neuronal activity, but the potential role of lncRNAs in depression remains largely unknown. Here, we identified that lncRNA Gm2694 was increased in the medial prefrontal cortex (mPFC) of male mice subjected to chronic social defeat stress (CSDS). The down-regulation of Gm2694 in the mPFC alleviated CSDS-induced depressive-like behaviors through enhanced excitatory synaptic transmission. Furthermore, we found that Gm2694 preferentially interacted with the carboxyl-terminal domain of 78-kilodalton glucose-regulated protein (GRP78), which abrogated GRP78 function and disrupted endoplasmic reticulum homeostasis, resulting in a reduction of the surface expression of AMPA receptors (AMPARs). Overexpression of GRP78 in the mPFC promoted the surface expression of AMPARs and attenuated the CSDS-induced depressive-like behaviors of mice. Together, our results unraveled a previously unknown role of Gm2694 in regulating endoplasmic reticulum homeostasis and excitatory synaptic transmission in depression.

Noncoding RNAs: Emerging regulators of behavioral complexity

“…Chen et al discovered its role in chronic social defeat stress (CSDS) induced depressive behavior in mice. CSDS-treated mice exhibit a poor social interaction ratio and a lower sucrose preference test in social interaction test and sucrose preference test, respectively, indicative of depression (Chen et al, 2022). Gm2694 is expressed in the neurons, microglia, and astrocytes of the mPFC and is localized in the endoplasmic reticulum (ER) and Golgi apparatus.…”

“…The perturbation of Gm2694 in the cerebellum is shown to modify the synapse stability (Wang et al, 2021). On the other hand, the perturbation of Gm2694 expression in the mPFC was shown to be involved in depressive‐like behaviors (Chen et al, 2022; see details below).…”

“…This lncRNA is also expressed in the PFC, and its levels are increased in the mPFC in mice exposed to chronic stress. mPFC‐specific knockdown of lncRNA‐PM enhances synaptic transmission, leading to social isolation, and depression‐like symptoms (Chen et al, 2022). Several lncRNAs are known to affect social behavior in mice.…”

“…Its upregulation in CSDS‐treated mice abrogates ER homeostasis, activating the Unfolded protein response (UPR) signaling in the ER lumen, which reduces AMPAR‐mediated miniature excitatory postsynaptic currents (mEPSCs). CSDS‐treated mice also show an increased dendritic density in the mPFC (Chen et al, 2022).…”

Perspective and Therapeutic Potential of the Noncoding RNA–Connexin Axis

“…lncRNA CCRR binds to the Cx43-interacting protein CIP85 and prevents the endocytic trafficking of Cx43, thereby controlling the membrane distribution of Cx43 and gap junction functioning [ 44 ]. Similarly, lncRNA Gm2694 interacts with the chaperone protein GRP78 to trigger an unfolded protein response, which is associated with endoplasmic reticulum disruption [ 55 ]. miRNAs that interact with proteins are involved in the crucial mechanism of RNA splicing [ 56 ].…”