Absence of Wdr13 Gene Predisposes Mice to Mild Social Isolation – Chronic Stress, Leading to Depression-Like Phenotype Associated With Differential Expression of Synaptic Proteins

Abstract

We earlier reported that the male mice lacking the Wdr13 gene (Wdr13-/0) showed mild anxiety, better memory retention, and up-regulation of synaptic proteins in the hippocampus. With increasing evidences from parallel studies in our laboratory about the possible role of Wdr13 in stress response, we investigated its role in brain. We observed that Wdr13 transcript gets up-regulated in the hippocampus of the wild-type mice exposed to stress. To further dissect its function, we analyzed the behavioral and molecular phenotypes of Wdr13-/0 mice when subjected to mild chronic psychological stress, namely; mild (attenuated) social isolation. We employed iTRAQ based quantitative proteomics, real time PCR and western blotting to investigate molecular changes. Three weeks of social isolation predisposed Wdr13-/0 mice to anhedonia, heightened anxiety-measured by Open field test (OFT), increased behavior despair- measured by Forced swim test (FST) and reduced dendritic branching along with decreased spine density of hippocampal CA1 neurons as compared to wild-type counterparts. This depression-like-phenotype was however ameliorated when treated with anti-depressant imipramine. Molecular analysis revealed that out of 1002 quantified proteins [1% False discovery rate (FDR), at-least two unique peptides], strikingly, a significant proportion of synaptic proteins including, SYN1, CAMK2A, and RAB3A were down-regulated in the socially isolated Wdr13-/0 mice as compared to its wild-type counterparts. This was in contrast to the elevated levels of these proteins in non-stressed mutants as compared to the controls. We hypothesized that a de-regulated transcription factor upstream of the synaptic genes might be responsible for the observed phenotype. Indeed, in the socially isolated Wdr13-/0 mice, there was an up-regulation of GATA1 – a transcription factor that negatively regulates synaptic genes and has been associated with Major Depression (MD) in humans. The present study demonstrates significant genotype × enviornment interaction for Wdr13 gene as shown by the reversal in the expression levels of several synaptic proteins in the mutant vis-à-vis wild-type mouse when exposed to social isolation stress.

Phosphoproteomic profiling of the hippocampus of offspring rats exposed to prenatal stress

“…These main signaling pathways were related to the Adcy9, Apc, Cacna1c, Camk2a, Camk2b, Camk2g, Ctnnd2, Grin2a, and Stx1a proteins. According to previous reports, Cacna1c, Camk2a, Camk2g, Grin2a, and Stx1a are all candidate genes for depression (Calabrò et al., 2019 ; Y. Kim et al., 2016 ; Mitra et al., 2018 ; Wingo et al., 2018 ; Yawalkar et al., 2018 ). The correlation of Adcy9, Apc, Camk2b, Camk2g, and Ctnnd2 with the pathological mechanisms of depression was first reported in the present work.…”

WDR13: A Novel Gene Implicated in Non-Syndromic Intellectual Disability

“…Moreover, this research group showed that the lack of Wdr13 led to the up-regulated expression of multiple genes, including synaptic genes such as Syn1, Rab3a, Nrxn2, and Camk2a. Surprisingly, Wdr13 null mice demonstrate better results in the Morris water maze task of spatial memory than wild-type animals [ 17 ]. Another study indicates that a lack of WDR13 protein impairs memory and learning efficiency [ 18 ].…”

Hypothalamic protein profiling from mice subjected to social defeat stress

“…Samples were processed and analysis was carried out using methods described previously [ 24 ]. Data are available via ProteomeXchange with identifier PXD005644.…”