A vicious cycle of microglial dysfunction: bridging synaptic pruning and neuroinflammation across the neurodevelopmental continuum

Abstract

Rather than viewing classical neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and severe psychiatric illnesses like schizophrenia (SCZ) as isolated diagnostic silos, modern biological psychiatry increasingly conceptualizes them along a shared neurodevelopmental continuum. Although altered synaptic connectivity and sustained immune dysregulation are both well-documented pathological features, the mechanistic crosstalk between them remains incompletely understood. In this review, we propose that microglia occupy a central position at the interface of these processes because of their dual roles in circuit remodeling and immune surveillance. While individual components, including complement-mediated pruning and inflammasome activation, have been extensively studied, the novelty of our framework lies in integrating these fragmented findings into a cohesive, bidirectional Dysregulated Pruning-Neuroinflammation Cycle to describe how the disruption of microglial homeostasis can sustain a self-perpetuating pathological loop. In this model, the vicious cycle may be initiated through an Outside-In route in which environmental inflammatory insults disrupt synaptic pruning, or through an Inside-Out route in which aberrant synaptic elimination releases danger signals that promote neuroinflammation. By considering early-onset ASD and adolescent/early-adult-onset SCZ, we propose that the interplay among timing, patterning, and background biases neurodevelopmental trajectories toward distinct clinical outcomes. Accordingly, this model highlights disease-modifying therapeutic strategies aimed at restoring microglial homeostasis to potentially mitigate the self-sustaining pathology in these clinically significant neurodevelopmental and psychiatric disorders.