Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation

Kei-Ichi Katayama; Naoko Morimura; Katsunori Kobayashi; Danielle Corbett; Takehito Okamoto; Veravej G Ornthanalai; Hayato Matsunaga; Wakako Fujita; Yoshifumi Matsumoto; Takumi Akagi; Tsutomu Hashikawa; Kazuyuki Yamada; Niall P Murphy; Soichi Nagao; Jun Aruga

doi:10.1016/j.isci.2022.104604

Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation

iScience. 2022 Jun 14;25(7):104604. doi: 10.1016/j.isci.2022.104604. eCollection 2022 Jul 15.

Authors

Kei-Ichi Katayama¹, Naoko Morimura¹, Katsunori Kobayashi², Danielle Corbett³, Takehito Okamoto⁴, Veravej G Ornthanalai⁵, Hayato Matsunaga⁶, Wakako Fujita⁶, Yoshifumi Matsumoto¹, Takumi Akagi⁷, Tsutomu Hashikawa⁷, Kazuyuki Yamada⁸, Niall P Murphy⁵, Soichi Nagao⁴, Jun Aruga^{1

6}

Affiliations

¹ Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
² Department of Pharmacology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan.
³ Neurotherapeutics Research Group, School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Dublin 4, Ireland.
⁴ Laboratory for Motor Learning Control, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
⁵ Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
⁶ Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8523, Japan.
⁷ Support Unit for Neuromorphological Analysis, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.
⁸ Support Unit for Animal Experiments, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama 351-0198, Japan.

Abstract

SLITRK2 encodes a transmembrane protein that modulates neurite outgrowth and synaptic activities and is implicated in bipolar disorder. Here, we addressed its physiological roles in mice. In the brain, the Slitrk2 protein was strongly detected in the hippocampus, vestibulocerebellum, and precerebellar nuclei-the vestibular-cerebellar-brainstem neural network including pontine gray and tegmental reticular nucleus. Slitrk2 knockout (KO) mice exhibited increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber-CA3 synapses with reduced sensitivity to serotonin. A serotonin metabolite was increased in the hippocampus and amygdala, and serotonergic neurons in the raphe nuclei were decreased in Slitrk2 KO mice. When KO mice were treated with methylphenidate, lithium, or fluoxetine, the mood stabilizer lithium showed a genotype-dependent effect. Taken together, Slitrk2 deficiency causes aberrant neural network activity, synaptic integrity, vestibular function, and serotonergic function, providing molecular-neurophysiological insight into the brain dysregulation in bipolar disorders.

Keywords: Cell biology; Molecular physiology; Neuroscience.