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

Molecular Psychiatry volume 28, pages 3994–4010 (2023)Cite this article

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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.

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Fig. 1: Behavioral alterations in MAP6−/− and Kv3.1−/− mice.
Fig. 2: MAP6 deletion markedly reduces Kv3.1b channel level in PV+ GABAergic interneurons.
Fig. 3: MAP6 directly binds Kv3.1 channel N-terminus.
Fig. 4: Two MAP6 Mn modules bind both monomers and tetramers of Kv3.1 T1 domain.
Fig. 5: MAP6 binding regulates the protein levels of Kv3.1b channels in the soma and axonal terminals of primary cultured neurons.
Fig. 6: AAV-mediated knockdown of MAP6 in the amygdala reduced risk avoidance in mice and Kv3.1b channel level in infected neurons.
Fig. 7: Deleting MAP6 in the hippocampus induced hyperactivity and memory deficits in mice, and increased the activity of hippocampal CA3 pyramidal neurons.
Fig. 8: Kv3.1 knockdown in the amygdala or hippocampus reduced risk avoidance and induced hyperactivity.

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Acknowledgements

We thank Drs. Howard Gu for technical assistance in stereotaxic injection, David Arnold for technical assistance in rotarod, Laurence Coutellier for consultation in behavioral testing, and OSU Neuroscience Image Core (P30NS104177) for technical assistance in confocal microscopy. This work was supported, in part, by grants from NIH (R01NS093073) to CG. All animal experiments have been conducted in accordance with the NIH Animal Use Guidelines. The authors declare no competing financial interests.

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Author notes

  1. Joshua Barry

    Present address: 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

Authors and Affiliations

  1. Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA

    Di Ma & Chen Gu

  2. Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, 43210, USA

    Di Ma, Chao Sun, Rahul Manne, Joshua Barry, Houzhi Li & Chen Gu

  3. MCDB graduate program, The Ohio State University, Columbus, OH, USA

    Chao Sun & Chen Gu

  4. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA

    Tianqi Guo & Thomas Magliery

  5. Univ. Grenoble Alpes, Inserm, U1216, CEA, Grenoble Institut Neurosciences, 38000, Grenoble, France

    Christophe Bosc & Annie Andrieux

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Contributions

CG designed and supervised the research; DM, SC, JB, RM, HL, and CG performed experiments and made the figures; TG and TM performed the SPR experiment. CB and AA provided critical reagents and revised the manuscript. DM and CG wrote and revised the manuscript.

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Correspondence to Chen Gu.

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Ma, D., Sun, C., Manne, R. et al. A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory. Mol Psychiatry 28, 3994–4010 (2023). https://doi.org/10.1038/s41380-023-02286-7

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