Building and deconstructing epilepsy circuits using mice and human brain organoids
Epileptic seizures represent abrupt switches in brain state that often arise from a background of normal activity to interrupt ongoing processes before terminating just as quickly. Understanding how these events are generated and maintained is an important clinical and basic goal. Using mice carrying a mutation in the voltage-gated sodium channel Nav1.6 (Scn8a) as a model of absence epilepsy, we show how seizures can be caused by a breakdown in synaptic inhibition within a specific pathway of a rhythm-generating circuit within the thalamus. This pathway, we propose, represents an endogenous seizure suppressing component of the thalamocortical circuit that may also constrain synchronous features of physiological rhythms. Interestingly, while conducive of absence seizures via increased thalamic excitability, these Scn8a mutations also effectively suppress cortically-driven convulsive seizures. We find that Scn8a-dependent cortical seizure suppression arises via two co-conspiring factors, reduced excitatory neuron output and reduced disinhibition (i.e. reduced inhibition of inhibitory cells).
Lastly, I will share with you our recent efforts to understand epilepsy pathogenesis using a novel 3D human cell culture model of the developing cortex that is generated from induced pluripotent stem cells. Using this system, we find that an epilepsy mutation in the L-type calcium channel Cav1.2 (CACNA1C) alters the formation of cortical networks, in part, by impairing the migratory behavior and excitability of integrating inhibitory cells.
Together these results demonstrate that the origins of some epilepsies can be traced back to the very earliest phases of circuit assembly, often before seizures or other overt aspects of the disorder are apparent and highlight the need to continue to advance new methods to understand brain development and function.
Christopher Makinson, PhD, is a research fellow in the Department of Neurology at Stanford University working under the mentorship of Drs John Huguenard and Sergiu Pasca. His research focuses on understanding the role of ion-channels in development and neurological diseases such as epilepsy using rodent and human brain organoid models.
During his postdoc with Dr John Huguenard, Dr Makinson studied how mutations in ion-channels cause absence epilepsy. These studies provided insight into how the thalamus controls network synchrony and identified a novel mechanism of seizure generation. Dr Makinson also worked with Dr Sergiu Pasca to develop some of the first human induced pluripotent stem cell-derived brain organoids.
Next year Dr. Makinson will join the faculty of the departments of Neurology and Neuroscience at Columbia University where he will continue to study the role of ion-channels in early development.