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

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. [Display omitted] •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 Yamamoto et al. find that during acute inflammation in the cerebellum, both non-synaptic (intrinsic excitability) and synaptic plasticity are induced by inflammatory cytokines released from microglia via TLR4 pathways. Tests of animal behaviors and rs-fMRI suggest a reduction of animal behavior and abnormal brain functional connectivity, which immune suppression recovered.