BDNF and JNK signalling modulate cortical interneuron and perineuronal net development: implications for schizophrenia-linked 16p11.2 duplication syndrome

Willis, A., Pratt, J. A. and Morris, B. J. (2021) BDNF and JNK signalling modulate cortical interneuron and perineuronal net development: implications for schizophrenia-linked 16p11.2 duplication syndrome. Schizophrenia Bulletin, 47(3), pp. 812-826. (doi: 10.1093/schbul/sbaa139) (PMID:33067994)

Abstract

Schizophrenia (SZ) is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication (DUP) of chr.16p11.2. SZ is characterized by cortical gamma-amino-butyric acid (GABA)ergic interneuron dysfunction and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain-derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signaling. In mice reproducing the 16p11.2 DUP, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs, which persist into adulthood. Prefrontal cortex parvalbumin (PVB) expression is reduced, while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signaling in the regulation of PVB interneurons. Our work implicates TAOK2-JNK signaling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with SZ risk causes long-lasting disruption in cortical interneurons.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Pratt, Dr Judith and Willis, Ashleigh and Morris, Professor Brian
• Authors: Willis, A., Pratt, J. A., and Morris, B. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Schizophrenia Bulletin
• Publisher: Oxford University Press
• ISSN: 0586-7614
• ISSN (Online): 1745-1701
• Published Online: 17 October 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Schizophrenia Bulletin 47(3): 812-826
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172418		Characterising mice syntenic for human 16p11.2 in relation to schizophrenia and autism. ID 13267	Brian Morris	Medical Research Council (MRC)	MR/N012704/1	NP - Centre for Neuroscience