TAOK2 controls synaptic plasticity and anxiety through ERK and calcium signaling

The kinase TAOK2 regulates dendritic architecture and synaptic plasticity and is implicated in neurodevelopmental and neuropsychiatric disorders, including autism and schizophrenia. Here, we investigated TAOK2 function by creating an Emx1-Cre-driven, excitatory neuron-specific conditional Taok2 knockout (Taok2 cKO) mouse line. Pathway profiling in Taok2 cKO primary cortical neurons revealed impaired ERK/MAPK and calcium signaling after AMPA, BDNF, or bicuculline stimulation. These results were validated by reduced p-ERK1/2 protein levels and decreased calcium flux. Cultured Taok2 cKO neurons displayed reduced synaptic density and connectivity. Single-nucleus RNA sequencing of medial prefrontal cortex identified dysregulated gene expression enriched for postsynaptic MAPK and calcium pathways within cortical layers 2/3 and 4/5. Taok2 cKO mice exhibited an anxiety-related thigmotactic behavior in the open field test. Our findings demonstrate that TAOK2 loss in excitatory cortical neurons disrupts synaptic signaling and connectivity, driving behavioral abnormalities, and position TAOK2 as a potential drug target for neuropsychiatric disorders.