The potential role of aberrant microglial synaptic pruning in the neurodevelopmental pathogenesis of tourette syndrome

Abstract

Tourette syndrome is a neurodevelopmental disorder traditionally attributed to dopamine system hyperactivity within the cortico-striato-thalamo-cortical circuitry. However, classical neurotransmitter hypotheses fail to fully explain the spatiotemporal and developmental specificities of the disorder. Consequently, research focus has shifted toward the neuroimmune microenvironment, specifically the role of microglia. This review aims to comprehensively explore the potential mechanisms of microglia-mediated aberrant synaptic pruning in the pathogenesis of tourette syndrome and to evaluate emerging therapeutic strategies. Methodologically, the study employs a narrative review approach to synthesize current neuroimmunobiology literature to reconstruct the pathological trajectory from early immune dysregulation to targeted interneuron impairment. Additionally, it conceptually explores natural product active monomers through a multi-target network pharmacology framework and assesses the translational potential of engineered nanodelivery systems. The findings indicate that genetic susceptibilities, such as histidine decarboxylase gene mutations, interact with environmental stressors, like maternal immune activation, to induce a chronically primed state in basal ganglia microglia. These primed innate immune cells are hypothesized to execute excessive synaptic pruning against highly vulnerable parvalbumin-expressing fast-spiking interneurons, a process significantly facilitated by the pathological downregulation of presynaptic protective signals. The physical loss of this local gamma-aminobutyric acid-ergic inhibitory network attenuates feedforward inhibition on medium spiny neurons, potentially contributing to macroscopic dopaminergic disinhibition. To address these mechanisms, multi-target natural therapies delivered via intelligent nanoplatforms present a theoretically promising approach to penetrate the blood–brain barrier and reverse pathological microglial phenotypes. Ultimately, this manuscript proposes a perspective of tourette syndrome as a microstructural developmental disorder of the circuitry rather than a mere neurotransmitter imbalance, providing a critical theoretical foundation for developing precise, next-generation neuroimmune-modulating interventions.