Thalamic Reticular Dysfunction as a Circuit Endophenotype in Neurodevelopmental Disorders

Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate-level of explanatory description that links gene to behavior as well as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g. macroscopic rhythms, goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a ‘circuit endophenotype’ would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.