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

Willis, Ashleigh and Pratt, Judith A and Morris, Brian J (2020) BDNF and JNK-signalling modulate cortical interneuron and perineuronal net development: implications for schizophrenia-linked 16p11.2 duplication syndrome. Schizophrenia Bulletin. sbaa139. ISSN 0586-7614

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    Abstract

    Schizophrenia is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication of chr.16p11.2. Schizophrenia is characterised by cortical GABAergic 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 signalling. In mice reproducing the 16p11.2 duplication, 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 expression is reduced while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signalling in the regulation of parvalbumin interneurons. Our work implicates TAOK2-JNK signalling 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 schizophrenia risk causes long-lasting disruption in cortical interneurons.