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

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.

Enzymatic Degradation of Cortical Perineuronal Nets Reverses GABAergic Interneuron Maturation

“…The role of JNK signalling in several developmental processes within the CNS has become apparent [70][71][72][73][74][75]. Our previous work has highlighted JNK and other MAPK signalling molecules, including TAOK2 and ERK, as key players in the maturation of GABAergic interneurons [76]. More specifically, our work has revealed a modulatory role for JNK in the development and regulation of PNNs.…”

“…Our previous work has highlighted that BDNF treatment of immature primary cortical neuronal cultures accelerates cortical interneuron maturation, and in particular, increases PNN density in a JNK-dependent manner [76]. This work has also implicated TAOK2, an upstream activator of JNK, in the appropriate development of PVB + interneurons and PNNs.…”

“…Previous evidence has linked the JNK signalling pathway, along with upstream kinases, to key processes in GABAergic interneuron development [72][73][74]120] including the regulation of various PNN components throughout development [76]. Moreover, members of the JNK family have been linked to synaptic plasticity [70,[121][122][123][124][125].…”

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

“…Furthermore, TAO2 may play roles in the regulation of neuronal maturation. A recent study showed that BDNF could regulate cortical GABAergic interneuron maturation in a TAO2-JNK signaling pathway in a 16p11.2 duplication mouse model (Willis et al, 2020). Cultured neurons from 16p11.2 duplication mice exhibit an abnormal interneuron developmental phenotype that may be involved in a premature closure of the critical period which is likely to be driven by OE of TAO2 and the subsequent over-activity of JNK, since pharmacological inhibition of TAO kinase could alleviate the 16p11.2 duplication phenotype.…”

“…Cultured neurons from 16p11.2 duplication mice exhibit an abnormal interneuron developmental phenotype that may be involved in a premature closure of the critical period which is likely to be driven by OE of TAO2 and the subsequent over-activity of JNK, since pharmacological inhibition of TAO kinase could alleviate the 16p11.2 duplication phenotype. Given the importance of parvalbumin (PBV+) interneurons in the regulation of excitatory/inhibitory balance within cortical regions, accelerated GABAergic development by TAO2 over-activity may lead to dysregulated network activity and synaptic connectivity (Willis et al, 2020). In addition, it was reported that OE of human TAO1 could also prevent maturation of cultured primary hippocampal neurons from mice (Woerden et al, 2021), while the role of JNKs is involvement is yet to be determined.…”