Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.

A pivotal role of microglia is the maintenance of brain homeostasis, but the function is severely altered in the brains with psychiatric disorders such as schizophrenia spectrum disorders. Previous pathological and physiological findings indicate a localized deficit in the cerebellum of the patients. However, it is unknown if the accumulation of inflammatory stress alters microglia morphology, localization, molecular expression pattern, and phenotype. Here, using translational mouse models that exploit known risk factors for mental disorders: maternal infection and repeated social defeat stress, we investigated the brain immune environment of psychiatric disorder models with multiple immune stress. The synergy of maternal immune activation and repeated defeat stress on mice brought forth reactive microglia specifically in the cerebellum. The increase in the reactive microglia in 2HIT correlated with cerebellar Purkinje neuron loss. Highly-multiplexed imaging mass cytometry with originally-customized 26 markers demonstrated a TREM2-positive immune-cell population of disease-associated microglia/macrophages (DAMIMCs) being close at near-vasculature. Single-cell proteomic clustering indicates sIL-6R- and TGFBR2-signaling with cell transition from progenitor cells to mature DAMIMCs, which implies synergistic disruption of neurophysiological properties and functioning in the 2HIT cerebellum. Our study identifies the distinct immune cells in the cerebellum, which may influence cognition and behavior.