Immunity meets inhibition: Immunomodulation of cortical inhibitory synaptic networks

Abstract

Interactions between the nervous and immune systems are increasingly recognized as pivotal in normal physiology, brain function, and behavior. This review explores an emerging frontier in neurobiology focusing on the regulation of cortical inhibitory synapses and circuits by immune mediators and effectors, with a particular emphasis on microglia and meningeal immune cells. Microglia, the primary immune cells in the brain parenchyma, regulate inhibitory synapse development and function. Recent evidence revealed the crucial role of gamma-aminobutyric acid (GABA) signaling in mobilizing microglia and modulating their interactions with inhibitory neurons. These include physical shielding, remodeling or stripping of inhibitory synapses, and releasing soluble factors. Meningeal immune cells, comprising innate and adaptive populations, also influence cortical inhibition under physiological conditions via secretion of cytokines such as interferon-gamma and interleukins. This review highlights the mechanisms through which immune cells modulate cortical inhibition, and more broadly, the role of neuroimmune interactions in normal brain development and function.