The neuroimmunological synapse: From synaptic homeostasis to brain disease

Abstract

Microglia are the resident immune cells of the central nervous system (CNS). They play fundamental roles in active immune defense and neuroinflammatory responses. Historically, it has been assumed that microglia exist in a resting state until pathological stimuli trigger their activation. However, a series of recent landmark studies revealed important physiological functions of microglia in neural development, synaptic remodeling and homeostasis. Likewise, accumulating evidence suggests that immune mediators and inflammatory cytokines may assert physiological roles in synaptic transmission and plasticity. Hence, the concept of a neuroimmunological synapse has started to emerge based on the observation that microglial factors, such as tumor necrosis factor alpha (TNFα) modulate plasticity at tripartite synapses. In pathological conditions, in which microglia are activated by non-physiological stimuli (and/or circulating immune mediators and immune cells enter the CNS), homeostasis between microglia, astrocytes and neurons at synaptic sites will be altered, which may initiate, promote or sustain pathological brain states.