Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Liu, Y.; Huang, M.-Q.; Zhang, Y.-C.; Jia, Z.-R.; Min, X.; Zhou, Z.-Y.; Chen, J.-Y.; Zong, F.-J.; Gao, J.; Xu, Y.-W.; Wang, T.; Zhang, Y.-Y.; He, K.-W.

doi:10.64898/2026.10.25.761716

bioRxiv · 10.64898/2026.10.25.761716

Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Liu, Y.·Huang, M.-Q.·Zhang, Y.-C.·Jia, Z.-R.·Min, X.·Zhou, Z.-Y.·Chen, J.-Y.·Zong, F.-J.·Gao, J.·Xu, Y.-W.·Wang, T.·Zhang, Y.-Y.·He, K.-W.

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Abstract

Transforming growth factor {beta}-activated kinase 1 (TAK1) is a serine/threonine kinase best known for its roles in immune and stress-response signaling, yet its physiological function in mature neurons remains poorly understood. Here we identify neuronal TAK1 as a regulator of excitatory synaptic integrity, hippocampal plasticity and memory. Conditional reduction of TAK1 in forebrain excitatory neurons impaired short- and long-term memory and was accompanied by attenuated long-term potentiation in the hippocampus. At the cellular level, TAK1 deficiency reduced dendritic spine density and suppressed excitatory synaptic transmission, whereas genetic or pharmacological disruption of TAK1 kinase activity recapitulated these synaptic deficits. Mechanistically, TAK1 localized to the postsynaptic compartment of excitatory synapses and associated with PSD-95. Phosphoproteomic analysis of isolated postsynaptic density fractions revealed coordinated changes in synaptic phosphorylation following TAK1 reduction, including decreased phosphorylation of the NMDA receptor subunit GluN2B at serine 920. Analyses of phosphodeficient and phosphomimetic GluN2B mutants supported a role for S920 phosphorylation downstream of TAK1 in maintaining dendritic spine density, excitatory synaptic transmission and spontaneous synaptic calcium activity. Notably, synaptic TAK1 level was reduced in the aged hippocampus. Re-expressing neuronal TAK1 in aged mice increased dendritic spine density, enhanced hippocampal synaptic plasticity, and improved memory performance. Together, these findings define a postsynaptic TAK1-GluN2B signaling axis that supports excitatory synaptic function and suggest that reduced synaptic TAK1 signaling may contribute to hippocampal vulnerability during aging.

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Liu, Y., Huang, M.-Q., Zhang, Y.-C., Jia, Z.-R., Min, X., Zhou, Z.-Y., Chen, J.-Y., Zong, F.-J., Gao, J., Xu, Y.-W., Wang, T., Zhang, Y.-Y., He, K.-W.. 2026-10-26. Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging. https://doi.org/10.64898/2026.10.25.761716

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