TNiK Is Required for Postsynaptic and Nuclear Signaling Pathways and Cognitive Function

Marcelo P. Coba,^1,2 * Noboru H. Komiyama,^1,3 * Jess Nithianantharajah,^1,3 * Maksym V. Kopanitsa,^1,4 Tim Indersmitten,⁵ Nathan G. Skene,¹ Ellie J. Tuck,^1,4 David G. Fricker,^1,4 Kathryn A. Elsegood,^1,3 Lianne E. Stanford,¹ Nurudeen O. Afinowi,^1,4 Lisa M. Saksida,⁶ Timothy J. Bussey,⁶ Thomas J. O'Dell,⁷ , and Seth G.N. Grant^1,3,6

¹Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom, ²Zilkha Neurogenetic Institute, Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, Los Angeles, California 90089, ³Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, United Kingdom, ⁴Synome Ltd, Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom, ⁵Interdepartmental PhD Program for Neuroscience, University of California Los Angeles, Los Angeles, California 90095, ⁶Department of Experimental Psychology and The MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, and ⁷Department of Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Dr. Seth G. N. Grant, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. Email: seth.grant{at}ed.ac.uk

Abstract: Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3β and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object-location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3β inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes.

Correspondence should be addressed to Dr. Seth G. N. Grant, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. Email: seth.grant{at}ed.ac.uk