wdr13 knockout mice develops MD like phenotype on chronic stress

WDR13 expresses from the X chromosome and has a highly conserved coding sequence. There have been multiple associations of WDR13 with memory and psychiatric disorders. However, its detailed function in context of brain and behavior remains unknown. We characterized the behavioral phenotype of male mice lacking the homologue of WDR13 gene (Wdr13-/0). Mice were evaluated for changes in anxiety, learning and memory, and chronic stress induced behavioral deficits. Taking cue from analysis of its expression in the brain, we chose hippocampus and pre-frontal cortex for molecular studies to delineate its function. In the absence of Wdr13, there was a significant upregulation of synaptic proteins, viz., SYN1, RAB3A, CAMK2A etc accompanied with better memory retention in mice. Interestingly, three weeks social isolation stress resulted in downregulation of aforementioned synaptic proteins, decreased exploration time in central area of Open field test, increased immobility in Forced swim test, and reduced dendritic arborations of hippocampal CA1 neurons- hallmarks of Major Depressive Disorder (MDD) in Wdr13-/0 mice. This phenotype could be rescued by short imipramine treatment. We hypothesise that one of the key factors behind the MDD like phenotype in these mice was upregulation of transcription factor GATA1. Parallel work from our lab has indicated WDR13 to interact with multiple nuclear receptors and acting majorly as a co-repressor. Absence of Wdr13 resulted in de-regulated expression of a number of genes including multiple synaptic genes leading to observed phenotypes. Summarily, our data provides functional evidence for the role of Wdr13 in memory retention and in withstanding chronic stress induced depression.

WDR13基因定位于X染色体并表达，其编码序列具有高度保守性。目前已有多项研究将WDR13与记忆功能及精神类疾病建立关联。然而，其在大脑与行为调控中的具体功能仍未明确。本研究对缺失WDR13基因同源物的雄性小鼠（Wdr13-/0）的行为表型进行了系统表征。我们通过多项实验评估了该小鼠的焦虑水平、学习记忆能力以及慢性应激诱导的行为缺陷变化。基于对其在大脑中表达谱的分析，我们选取海马体与前额叶皮层开展分子研究，以阐明其功能机制。在缺失Wdr13的小鼠中，突触相关蛋白（如SYN1、RAB3A、CAMK2A等）的表达显著上调，同时小鼠的记忆保持能力得到改善。值得注意的是，为期三周的社交隔离应激可诱导Wdr13-/0小鼠出现以下变化：上述突触蛋白表达下调、旷场实验中中央区域探索时长减少、强迫游泳实验中不动时间增加，以及海马CA1神经元树突分支减少——这些均为重度抑郁症（Major Depressive Disorder, MDD）的特征性表型。该类表型可通过短期丙咪嗪（imipramine）治疗得到逆转。我们推测，此类小鼠出现类重度抑郁症表型的关键诱因之一为转录因子GATA1的表达上调。本实验室的平行研究表明，WDR13可与多种核受体相互作用，主要作为辅阻遏因子发挥调控功能。Wdr13的缺失会导致包括多个突触相关基因在内的大量基因表达失调，进而引发本研究观测到的各类表型。综上，本研究的数据为WDR13在记忆保持以及对抗慢性应激诱导的抑郁中的作用提供了直接的功能学证据。