Cell Reports
Volume 28, Issue 11, 10 September 2019, Pages 2923-2938.e8
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Article
Microglia-Triggered Plasticity of Intrinsic Excitability Modulates Psychomotor Behaviors in Acute Cerebellar Inflammation

https://doi.org/10.1016/j.celrep.2019.07.078Get rights and content
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Highlights

  • Purkinje cell-intrinsic plasticity is induced by TNF-α released from microglia

  • TNF-α and ATP following microglial activation facilitate synaptic transmission

  • Acute inflammation in the anterior cerebellum resulted in depression-like behaviors

  • Suppression of microglia rescued both hyperexcitability and behavioral modulation

Summary

Cerebellar dysfunction relates to various psychiatric disorders, including autism spectrum and depressive disorders. However, the physiological aspect is less advanced. Here, we investigate the immune-triggered hyperexcitability in the cerebellum on a wider scope. Activated microglia via exposure to bacterial endotoxin lipopolysaccharide or heat-killed Gram-negative bacteria induce a potentiation of the intrinsic excitability in Purkinje neurons, which is suppressed by microglia-activity inhibitor and microglia depletion. An inflammatory cytokine, tumor necrosis factor alpha (TNF-α), released from microglia via toll-like receptor 4, triggers this plasticity. Our two-photon FRET ATP imaging shows an increase in ATP concentration following endotoxin exposure. Both TNF-α and ATP secretion facilitate synaptic transmission. Region-specific inflammation in the cerebellum in vivo shows depression- and autistic-like behaviors. Furthermore, both TNF-α inhibition and microglia depletion revert such behavioral abnormality. Resting-state functional MRI reveals overconnectivity between the inflamed cerebellum and the 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

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6

These authors contributed equally

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