Neuroimmune remodeling of cortico-striatal circuits in pediatric Tourette syndrome: from immune-to-brain signaling to inhibitory network dysfunction

Tourette syndrome (TS) usually starts in childhood and often becomes less impairing during adolescence. Its biology must therefore explain tic onset, short-term changes in expression, and long-term persistence as separate outcomes. Pediatric studies report cytokine, lymphocyte, and antibody differences, but these descriptive profiles do not establish functional immune dysregulation. This review examines how peripheral signals might affect vascular interfaces, glial function, and maturation of cortico-striatal inhibitory networks. Large prospective studies have found no general association between group A streptococcal exposure and tic onset or exacerbation. Adult striatal tissue studies identify interneuron-associated abnormalities alongside microglial immune-response programs; they provide adult endpoints, not evidence of a childhood causal sequence. Experimental work, predominantly outside TS, identifies distinct mechanisms involving inhibitory synapse formation, selective removal, and receptor regulation. None has been demonstrated as an immune-mediated developmental mechanism in pediatric TS. Sex, pubertal stage, genetic susceptibility, and co-occurring attention-deficit/hyperactivity disorder or obsessive-compulsive disorder may modify the proposed relationships. We prioritize longitudinal noninvasive measures of regional inhibitory physiology, paired with standardized immune measurements and distinct measures of tic frequency, severity, impairment, and remission. These observations could test temporal predictions without pediatric tissue, but would require cell-specific perturbation and rescue in appropriate experimental systems to support a mechanistic interpretation. The framework guides research questions and does not support immune-targeted treatment in typical TS.