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A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory.

ABSTRACT: The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated K⁺ (Kv) channel, but their relationship and functions in behavioral regulation are often not known. Here we report that MAP6 stabilizes Kv3.1 channels in parvalbumin-positive (PV+ ) fast-spiking GABAergic interneurons, regulating behavior. MAP6^-/- and Kv3.1^-/- mice display similar hyperactivity and avoidance reduction. Their proteins colocalize in PV+ interneurons and MAP6 deletion markedly reduces Kv3.1 protein level. We further show that two microtubule-binding modules of MAP6 bind the Kv3.1 tetramerization domain with high affinity, maintaining the channel level in both neuronal soma and axons. MAP6 knockdown by AAV-shRNA in the amygdala or the hippocampus reduces avoidance or causes hyperactivity and recognition memory deficit, respectively, through elevating projection neuron activity. Finally, knocking down Kv3.1 or disrupting the MAP6-Kv3.1 binding in these brain regions causes avoidance reduction and hyperactivity, consistent with the effects of MAP6 knockdown. Thus, disrupting this conserved cytoskeleton-membrane interaction in fast-spiking neurons causes different degrees of functional vulnerability in various neural circuits.

SUBMITTER: Ma D

PROVIDER: S-EPMC10905646 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory.

Ma Di D Sun Chao C Manne Rahul R Guo Tianqi T Bosc Christophe C Barry Joshua J Magliery Thomas T Andrieux Annie A Li Houzhi H Gu Chen C

Molecular psychiatry 20230901 9

The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated K+ (Kv) channel, but their relationship and functions in behavioral regulation are often not known. Here we report that MAP6 stabilizes Kv3.1 channels in parvalbumin-positive (PV+ ) fast-spiking GABAergic interneurons, regulating behavior. MAP6-/- and Kv3.1-/- mice display similar hyperactivity a ...[more]

PMID: 37833406

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Dataset Information

A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory.

Publications

A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory.

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