Science Topics – 130

Acute cerebellar inflammation and cerebellar hyperexcitability may cause depressive-like behaviors
Masamichi Yamamoto1, Minsoo Kim2,3, Hirohiko Imai4, (Gen Ohtsuki2,5)

In these days, the cerebellum is not merely involved in motor function, but works in coordination with various brain regions. It is beginning to be understood that the cerebellum is the part responsible for higher-order brain functions such as visual response, pain, emotion, reward learning, and motor planning. Such a part responsible for higher-order functions of the cerebellum leads to the expression of action as a coordinated activity with the cerebral cortex. Recently, it has been pointed out that the autistic symptoms (such as decreased communication ability, decreased intellect, less interest in surroundings but strong adherence to specific things, etc.), which are included in pervasive developmental disorder (PDD), relate to the cerebellar dysfunction. However, the details of signal transduction between these functional areas have not been elucidated. In addition, although the pathogenic infection that occurs in the cerebellum is a rare infection, the physiological mechanisms which affect the nervous system and how it relates to the mental activity of animals were completely unknown.

Microglia, immune cells in the brain, essentially respond to foreign body invasion (e.g., bacteria and viruses) and damage to the brain. They remove the invasive substances and damaged sites. On the other hand, excessive inflammation in the brain has been implicated in various mental disorders such as depression. In this project, we aimed to analyze acute cerebellar inflammation in a rodent model and restore its symptoms. We also aimed to clarify the signaling pathway of neuronal plasticity during the cerebellar acute inflammation.

Here, we showed that when cerebellar inflammation is induced, the excitability in the cerebellum increases excessively through a phenomenon called “intrinsic plasticity” (i.e., a long-lasting increase in firing frequency and membrane excitability of neurons) and that the animal's sociability, free-searching behavior, motivation etc decline through the inflammation in the anterior lobes of cerebellum. By showing the signal transduction involved in this excitability plasticity, we also demonstrated that it is possible to recover the behavioral abnormality by suppressing the neuro-immunity (microglia) and an inflammatory cytokine (tumor necrosis factor-α, TNF-α). These results indicate that the inflamed cerebellum is involved in behavioral impairments with similar symptoms to developmental disorders, such as depressive and autistic behaviors in rats. It was also noteworthy that the activity of the prefrontal cortex increased during cerebellar inflammation from our observation using functional magnetic resonance imaging (fMRI). Thus, the cerebellum was shown to be involved in higher-order brain function by its connection with the cerebrum. Microglia-triggered plasticity of intrinsic excitability modulates psychomotor behaviors in acute cerebellar inflammation.

Yamamoto M*, Kim M*, Imai H*, Itakura Y and Ohtsuki G . Cell Reports (2019) vol 28, pp 2923–2938, 2019. Cover article of the issue. *equal contribution. corresponding author.

1 Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto University Hospital
2 The Hakubi Center for Advanced Research, Kyoto University
3 Department of Molecular and Cell Physiology, Kyoto University Graduate School of Medicine
4 Department of Systems Science, Kyoto University Graduate School of Informatics
5 Department of Biophysics, Kyoto University Graduate School of Science