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

Abstract

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. : 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. A battery test of animal behaviors and rs-fMRI suggest a reduction of animal behavior and abnormal brain functional connectivity, which immune suppression recovered. Keywords: Purkinje cells, microglia, intrinsic plasticity, dendritic excitability, synaptic currents, cerebellum, inflammatory cytokines, functional connectivity, psychomotor behaviors