Wdr5 Modulates Synaptic Development and Memory Consolidation in the Hippocampus and Cerebral Cortex

WD-repeat domain 5 (Wdr5), a core component of the SET1/MLL family of histone methyltransferases, is widely involved in the regulation of development, epigenetic control, transcription, and cell division. Wdr5 has been linked to neurodevelopmental disorders characterized by intellectual disability and developmental delay-yet its regulatory roles in neurons remain poorly understood. Here, we report that postnatal deletion of Wdr5 in excitatory forebrain neurons impairs learning and memory in male Wdr5fl/fl; CaMKIIα-iCre conditional knockout (Wdr5 cKO) mice. We showed that the conditional Wdr5 knockout affects dendritic spine as well as synapse development in cortex and hippocampus. In addition, the expression profile of the hippocampus in response to contextual fear-conditioning tests was dysregulated in the Wdr5 cKO mice, including genes related to Notch signaling and mitochondrial respiratory. The recovery of the expression of the immediate early genes was also impaired in the Wdr5 cKO mice compared to the wild-type mice. Collectively, these findings identify Wdr5 as a critical regulator of synaptic development and memory consolidation.