PLEKHA2 plays an essential role in adult neurogenesis and synaptic plasticity in the hippocampus

The hippocampus is a principal brain region of adult neurogenesis and a key model for studying synaptic plasticity underlying learning and memory. Previously, our work suggested a role for the adaptor protein, PLEKHA2, in adult hippocampal neurogenesis; however, Plekha2 has been studied primarily in immune regulation, leaving its neural functions largely unexplored. To understand its functions in the brain, we generated a brain-specific Plekha2 conditional knockout (cKO) mouse model using CRISPR/Cas9 and Cre/loxP systems. Our findings showed that Plekha2 deletion resulted in reduced adult hippocampal neurogenesis, particularly impairing neuronal lineage entry and subsequent neuronal output. Electrophysiological recordings further revealed decreased excitability of dorsal, but not ventral, dentate granule cells, a region difference consistent with the higher endogenous Plekha2 expression in the dorsal hippocampus. Impaired synaptic plasticity, as indicated by a reduced paired-pulse ratio and attenuated long-term potentiation, was also observed. Behaviorally, Plekha2 cKO mice exhibited increased anxiety and impaired avoidance learning. To explore potential molecular mechanisms, RNA-sequencing identified down-regulated genes enriched for functions related to neuronal development, in line with the observed deficits in neurogenesis and synaptic functions, although the precise pathways remain unclear. Collectively, these findings establish Plekha2 as a critical regulator of adult hippocampal neurogenesis, synaptic plasticity, neuronal excitability, and behavior.