BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome.
BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome.
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DOI：
10.1093/schbul/sbaa139
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发表时间：
2021-04-29
影响因子：
6.6
通讯作者：
Morris BJ
中科院分区：
文献类型：
--
作者：
Willis A;Pratt JA;Morris BJ
精神分裂症（SZ）是一种由遗传和环境危险因素共同作用引起的神经发育障碍。其中一个最强的遗传风险变异是chr.16p11.2的重复（DUP）。SZ的特征是皮质γ -氨基丁酸（GABA）能神经元间功能障碍和周围细胞外基质结构，神经元周围网（PNNs）的破坏。gaba能中间神经元的发育成熟，以及由此导致的皮质可塑性关键期的关闭，是由脑源性神经营养因子（BDNF）调节的，尽管其机制尚不清楚。在这里，我们发现BDNF通过JNK信号传导促进gaba能中间神经元和PNN的成熟。在复制16p11.2 DUP的小鼠中，JNK上游激活因子Taok2过表达，我们发现JNK过度活跃，pnn存在发育异常，这种异常持续到成年。前额皮质小白蛋白（PVB）表达减少，PNN强度增加。此外，我们报道了TAOK2信号在PVB中间神经元调控中的独特作用。我们的研究表明TAOK2-JNK信号在皮层中间神经元和PNN的发育以及对BDNF的反应中起作用。它还表明，在与SZ风险相关的条件下，该通路的过度激活会导致皮质中间神经元的长期破坏。
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.
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