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 <i>Wdr13</i> gene (<i>Wdr13</i>^-/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 <i>Wdr13</i> in stress response, we investigated its role in brain. We observed that <i>Wdr13</i> 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 <i>Wdr13</i>^-/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 <i>Wdr13</i>^-/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 <i>Wdr13</i>^-/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 <i>Wdr13</i>^-/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 <i>Wdr13</i> 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.