TAOK2 controls synaptic plasticity and anxiety via ERK and calcium signaling

Journal article

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.

Authors: Ma, W; Warnhoff, I; Stephan, M; Ma, X; Dehne, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: iScience
• Volume: 28
• Issue: 11
• Pages: 113712
• Publication date: 2025-10-09
• Acceptance date: 2025-10-03
• DOI: 10.1016/j.isci.2025.113712
• EISSN: 2589-0042
• ISSN: 2589-0042
• Pmid: 41210984
• Language: English
• Keywords: Transcriptomics; Molecular Neuroscience; Cellular Neuroscience