Convergence of Thalamic Mechanisms in Genetic Epilepsies

Abstract The thalamus, a deep brain structure with broad connectivity, plays key roles in local and global rhythmic activity in sleep, arousal, and cognition. Disruptions in thalamic and thalamocortical circuits—and the ensuing hypersynchrony and hyperexcitability—have been widely studied in the context of genetic epilepsies and have garnered increasing interest in the context of acquired epilepsies. In this chapter, key structural, synaptic, cellular, and biophysical elements underlying the rhythmogenic properties of the thalamus are described, and then how diverse perturbations of these properties in rodent genetic models ultimately generate or facilitate seizures. The chapter briefly highlights recent studies which have identified mechanisms of thalamic involvement in the development or modulation of epilepsies acquired following incidents such as traumatic brain injury and ischemic stroke. Understanding how diverse etiologies converge upon thalamic hyperexcitability can pinpoint elements of vulnerability, resilience, redundancy, necessity, and sufficiency in the thalamocortical circuit. Understanding how the thalamus generates and modulates aberrant activity—even when it is not the primary or sole site of genetic perturbation—will be key to identifying therapeutic targets and paradigms to treat epilepsies. Such efforts will benefit from continued advancements in our knowledge of cell-type heterogeneity, meso- and macro-scale connectivity, and interspecies differences in the thalamus.