Regulation of Thalamic and Cortical Network Synchrony by Scn8a

• DOI: 10.1016/j.neuron.2017.01.031
• Publication Date: 2017-02-23T19:11:34Z
• Authors: Christopher D. Ma...; Brian S. Tanaka; Jordan M. Sorokin; Jennifer C. Wong; Catherine A. Chri...; Alan L. Goldin; Andrew Escayg; John R. Huguenard
• Keywords: 0301 basic medicine; thalamic reticular nucleus; seizure; Neurodegenerative; thalamocortical oscillations; Mice; 03 medical and health sciences; Thalamus; Seizures; 616; voltage-gated sodium channel; Genetics; 2.1 Biological and endogenous factors; Psychology; Animals; Aetiology; optogenetics; Epilepsy; Neurology & Neurosurgery; Biomedical and Clinical Sciences; Animal; Neurosciences; Electroencephalography; hypersynchrony; Brain Disorders; Disease Models, Animal; Absence; absence epilepsy; Phenotype; thalamic inhibition; Epilepsy, Absence; NAV1.6 Voltage-Gated Sodium Channel; RNAi; Neurological; Disease Models; Synapses; Biological psychology; Cognitive Sciences; Nerve Net

Voltage-gated sodium channel (VGSC) mutations cause severe epilepsies marked by intermittent, pathological hypersynchronous brain states. Here we present two mechanisms that help to explain how mutations in one VGSC gene, Scn8a, contribute to two distinct seizure phenotypes: (1) hypoexcitation of cortical circuits leading to convulsive seizure resistance, and (2) hyperexcitation of thalamocortical circuits leading to non-convulsive absence epilepsy. We found that loss of Scn8a leads to altered RT cell intrinsic excitability and a failure in recurrent RT synaptic inhibition. We propose that these deficits cooperate to enhance thalamocortical network synchrony and generate pathological oscillations. To our knowledge, this finding is the first clear demonstration of a pathological state tied to disruption of the RT-RT synapse. Our observation that loss of a single gene in the thalamus of an adult wild-type animal is sufficient to cause spike-wave discharges is striking and represents an example of absence epilepsy of thalamic origin.