TAOK2 controls synaptic plasticity and anxiety via ERK and calcium signaling

Ma, Wenbo; Warnhoff, Inanna; Stephan, Marius; Ma, Xiao; Dehne, Kerstin; Volkmann, Paul; Kannaiyan, Nirmal; Brankatschk, Ben; Jensen, Niels; Rossner, Moritz J.; Scheuss, Volker; Wehr, Michael C. (2025): TAOK2 controls synaptic plasticity and anxiety via ERK and calcium signaling. iScience, 28 (11): 113712. ISSN 25890042

Abstract

The kinase thousand and one amino acid kinase 2 (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 extracellular regulated kinase (ERK)/mitogen-activated protein kinase (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, drives behavioral abnormalities, and positions TAOK2 as a potential drug target for neuropsychiatric disorders.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Psychiatry and Psychotherapy
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892