BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome.

Ashleigh Willis,Brian J Morris,Judith A Pratt

doi:10.1093/schbul/sbaa139

Ashleigh Willis, Brian J Morris + Show 1 more

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https://doi.org/10.1093/schbul/sbaa139

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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.

Highlights

Schizophrenia (SZ) is a devastating mental illness with positive and negative symptoms combined with cognitive deficits.[1]
The 16p11.2 DUP region contains ~30 genes, including thousand and one kinase 2 (TAOK2) and mitogen-activated protein kinase 3 (MAPK3), both of which are implicated in neurodevelopmental disorders.14–16TAOK2 regulates mitogen-activated protein (MAP) kinase pathways, notably, the c-jun N-terminal kinase (JNK) pathway, where JNKs 1–3 are activated by upstream kinases mitogen-activated protein kinase kinase 4 (MKK4) or mitogen-activated protein kinase kinase 7 (MKK7).[17,18]
Primary mouse cortical cultures (14 days in vitro (DIV)) were stimulated with brain-derived neurotrophic factor (BDNF) to investigate their regulation of cortical GABAergic interneurons, along with inhibitors of the JNK signaling pathway (SP600125 [SP]), and 2 other well-characterized signaling pathways activated by BDNF-TrkB stimulation (ERK; PD98059 [PD], PI3K; wortmannin [WM])

Summary

Introduction

Schizophrenia (SZ) is a devastating mental illness with positive (eg, delusions and hallucinations) and negative (eg, social withdrawal and anhedonia) symptoms combined with cognitive deficits.[1]. The 16p11.2 DUP region contains ~30 genes, including thousand and one kinase 2 (TAOK2) and mitogen-activated protein kinase 3 (MAPK3) (encoding the kinases TAOK2 and ERK1), both of which are implicated in neurodevelopmental disorders.14–16TAOK2 regulates mitogen-activated protein (MAP) kinase pathways, notably, the c-jun N-terminal kinase (JNK) pathway, where JNKs 1–3 are activated by upstream kinases mitogen-activated protein kinase kinase 4 (MKK4) or mitogen-activated protein kinase kinase 7 (MKK7).[17,18] JNKs are strongly implicated in CNS development.[19,20,21,22] Interest in JNK is strengthened by an association between variations in the MAP2K7 gene (encoding MKK7) and prefrontal cortex (PFC) dysfunction in SZ.[23]. Brain-derived neurotrophic factor (BDNF) promotes GABAergic maturation in the hippocampus and cortex.[35,36,37] This is crucial for optimal development, as it leads to closure of the critical period of cortical plasticity,[38,39,40] the precise mechanisms are undefined. We investigated the potential disruption of cortical interneurons and PNN development in a 16p11.2 DUP mouse model and whether the same pathways might be involved

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