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

Autor: Ma D; Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA.; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA., Sun C; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA.; MCDB graduate program, The Ohio State University, Columbus, OH, USA., Manne R; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA., Guo T; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA., Bosc C; Univ. Grenoble Alpes, Inserm, U1216, CEA, Grenoble Institut Neurosciences, 38000, Grenoble, France., Barry J; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA.; IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Magliery T; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA., Andrieux A; Univ. Grenoble Alpes, Inserm, U1216, CEA, Grenoble Institut Neurosciences, 38000, Grenoble, France., Li H; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA., Gu C; Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA. gu.49@osu.edu.; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA. gu.49@osu.edu.; MCDB graduate program, The Ohio State University, Columbus, OH, USA. gu.49@osu.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 Sep; Vol. 28 (9), pp. 3994-4010. Date of Electronic Publication: 2023 Oct 13.
DOI: 10.1038/s41380-023-02286-7
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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