Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders

Recent advances in genomics have revealed a wide spectrum of genetic variants associated with neurodevelopmental disorders at an unprecedented scale. An increasing number of studies have consistently identified mutations-both inherited and de novo-impacting the function of specific brain circuits. This suggests that, during brain development, alterations in distinct neural circuits, cell types, or broad regulatory pathways ultimately shaping synapses might be a dysfunctional process underlying these disorders. Here, we review findings from human studies and animal model research to provide a comprehensive description of synaptic and circuit mechanisms implicated in neurodevelopmental disorders. We discuss how specific synaptic connections might be commonly disrupted in different disorders and the alterations in cognition and behaviors emerging from imbalances in neuronal circuits. Moreover, we review new approaches that have been shown to restore or mitigate dysfunctional processes during specific critical windows of brain development. Considering the heterogeneity of neurodevelopmental disorders, we also highlight the recent progress in developing improved clinical biomarkers and strategies that will help to identify novel therapeutic compounds and opportunities for early intervention.

Automated summary

Recent advances in genomics have revealed the genetic variations associated with neurodevelopmental disorders, indicating the importance of synaptic formation and circuit balance in these disorders. This review summarizes the research progress on synaptic and circuit mechanisms implicated in neurodevelopmental disorders and discusses the disruptions in synaptic connections and imbalances in neuronal circuits that contribute to cognitive and behavioral changes in different disorders. Furthermore, new approaches that can restore or mitigate dysfunctional processes and the development of improved clinical biomarkers and strategies for early intervention are highlighted.