Is there a glymphatic pathway to environmental risk in neurodevelopmental disorders?

The glymphatic system (GS) is a glia-dependent perivascular network that mediates cerebrospinal fluid-interstitial fluid exchange and facilitates the clearance of neurometabolites. GS transport is sleep-dependent, with waste elimination heightened during non-rapid eye movement sleep. Emerging evidence links GS dysfunction with neurodevelopmental disorders (NDDs), including autism spectrum disorder, schizophrenia, and attention-deficit/hyperactivity disorder, disorders that frequently co-occur with sleep disturbances. In parallel, multiple environmental toxicants have been associated with adverse neurodevelopment. This study aims to integrate current evidence on the interplay between toxicants, GS dysfunction, and NDDs, highlighting shared biological pathways and exploring potential therapeutic targets. Evidence gaps include the absence of studies directly investigating toxicant effects on GS within NDDs populations, limited longitudinal data across sensitive developmental windows, scarce integration of GS-sensitive imaging, cerebrospinal fuid (CSF) biomarkers, and underassessment of sex differences and exposure mixtures. Translational opportunities span sleep optimization and GS-targeted strategies (e.g., enhancing CSF transport); among pharmacologic candidates, the α2-adrenergic agonist dexmedetomidine shows sedative-anxiolytic, anti-inflammatory, and neuroprotective signals warranting investigation. This narrative review synthesizes current evidence and delineates priorities to test the exposome-glymphatic-neurodevelopment axis.