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

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