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Microglia-Triggered Plasticity of Intrinsic Excitability Modulates Psychomotor Behaviors in Acute Cerebellar Inflammation

92 Pages Posted: 8 Nov 2018 Sneak Peek Status: Published

See all articles by Masamichi Yamamoto

Masamichi Yamamoto

Kyoto University - Department of Nephrology

Minsoo Kim

Kyoto University - Hakubi Center for Advanced Research

Hirohiko Imai

Kyoto University - Department of Systems Science

Yamato Itakura

Kyoto University - Department of Biophysics

Gen Ohtsuki

Kyoto University - Hakubi Center for Advanced Research

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Abstract

Cerebellar dysfunction is involved in various psychiatric disorders, including autism-spectrum and depressive disorders. However, the physiological aspect is less-advanced. Here, we comprehensively investigated the immune-triggered hyperexcitability in the cerebellum. Activated microglia (MG) via exposure to bacterial endotoxin lipopolysaccharide or heat-killed Gram-negative bacteria induced a potentiation of the intrinsic excitability in Purkinje neurons, which was suppressed by MG-activity inhibitor and MG-depletion. An inflammatory cytokine, tumor necrosis factor-α (TNF-α) released from MG via toll-like receptor 4 triggered this plasticity. While our two-photon FRET ATP-imaging showed an increase in ATP concentration following endotoxin exposure, both TNF-α and ATP secretion facilitated synaptic transmission. Region-specific inflammation in the cerebellum in vivo showed depression- and autistic-like behaviors. Such behavioral modulation was reverted by both TNF-α-inhibition and MG-depletion. Resting-state functional MRI revealed overconnectivity between the inflamed cerebellum and prefrontal neocortical regions. Thus, immune activity in the cerebellum induces neuronal hyperexcitability and disruption of psychomotor behaviors in animals.

Keywords: Purkinje cells, microglia, intrinsic plasticity, dendritic excitability, synaptic currents, cerebellum, inflammatory cytokines, functional connectivity, psychomotor behaviors

Suggested Citation

Yamamoto, Masamichi and Kim, Minsoo and Imai, Hirohiko and Itakura, Yamato and Ohtsuki, Gen, Microglia-Triggered Plasticity of Intrinsic Excitability Modulates Psychomotor Behaviors in Acute Cerebellar Inflammation (November 7, 2018). Available at SSRN: https://ssrn.com/abstract=3280241 or http://dx.doi.org/10.2139/ssrn.3280241
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Masamichi Yamamoto

Kyoto University - Department of Nephrology

Yoshida-Honmachi
Sakyo-ku
Kyoto, 606-8501
United States

Minsoo Kim

Kyoto University - Hakubi Center for Advanced Research

Yoshidahonmachi
Sakyo Ward
Kyoto, 606-8501
Japan

Hirohiko Imai

Kyoto University - Department of Systems Science

Yoshida-Honmachi
Sakyo-ku
Kyoto, 606-8501
Japan

Yamato Itakura

Kyoto University - Department of Biophysics

Yoshida-Honmachi
Sakyo-ku
Kyoto, 606-8501
Japan

Gen Ohtsuki (Contact Author)

Kyoto University - Hakubi Center for Advanced Research ( email )

Yoshidahonmachi
Sakyo Ward
Kyoto, 606-8501
Japan

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