Microglia-triggered hyperexcitability in the cerebellum depresses animal behaviors

Abstract

Clinical studies have suggested that cerebellar dysfunction is involved in various psychiatric disorders, including autism spectrum disorders, dyslexia, and depressive disorders. However, the physiological aspect is less-advanced. Here, we comprehensively investigated the immune-triggered excitability plasticity in the cerebellum. Activated microglia (MG) via exposure to bacterial endotoxin lipopolysaccharide or heat-killed Gram-negative bacteria induced a potentiation of the excitability of Purkinje neurons, which was suppressed by MG-activity inhibitor and MG-depletion. An inflammatory cytokine, tumor necrosis factor- (TNF-) released from MG triggered this plasticity. While our new two-photon FRET ATP-imaging showed an increase in ATP concentration following endotoxin exposure, both TNF- and ATP secretion facilitated synaptic transmission. Inflammation in the cerebellar anterior vermis in vivo immobilized animals, and reduced sociability. Such abulia-like behavioral impairments were reverted by TNF--inhibition and MG-depletion. Resting-state functional MRI revealed overconnectivity between the inflamed cerebellum and prefrontal neocortical regions, which may underlie the psychomotor depressiveness in animals.