The Impact of Hemichannel-Mediated Neuroinflammation at Early Stages of CNS Ontogeny in the Development of Adult Neuropsychiatric Diseases

In pathological conditions, elevated activity of connexin and pannexin hemichannels facilitates Adenosine triphosphate (ATP) efflux and Ca²⁺ influx, activating metabolic pathways of neuroinflammation. While a small insult could result in a protective inflammatory response, more intense and/or prolonged insults induce cell death, causing tissue dysfunction. In the brain, different stressors elevate glucocorticoid (GC) levels that are sensed by mast cells and microglia, and this response persists for a long time, causing continuous inflammasome activation and release of IL-1β and IL-18. These proinflammatory cytokines, together with those released by mast cells, activate astrocytes and oligodendrocytes, which in turn release glutamate and ATP, and altogether reduce neuronal functionality and survival. The extent of neuroinflammation also depends on host features that result in different degrees of alterations during brain ontogeny, consequently changing the brain cytoarchitecture and leading to spectrums of behavioral diseases. Selective hemichannel blockers have been recently discovered and shown to reduce neuroinflammation, as well as neuronal suffering and symptoms linked to adult models of depression and epilepsy. These blockers can serve as tools to dissect the role of neuroinflammation in behavioral diseases. Early treatment during brain ontogeny could reduce detrimental impacts on the brain cytoarchitecture, inducing behavioral alterations elicited in adulthood.