Brain oscillations are critical for neural computation and can serve as a biomarker of excitatory-inhibitory (E/I) balance in neural circuits. Disruptions in oscillatory activity have been observed in individuals with autism spectrum disorder (ASD). Indeed, oscillatory dysregulation is thought to be a pathophysiological mechanism linking E/I imbalance with cognitive difficulties in ASD. In particular, a failure to generate gamma oscillations in early life is associated with language, cognitive and attention challenges characteristic of ASDs. However, uncovering the basic mechanisms linking E/I imbalance to oscillatory changes is difficult given the structural differences between human brain and animal models of ASD and the challenges of studying basic mechanisms in humans.

Ranmal Aloka Samarasinghe and colleagues have developed a novel brain organoid platform ideal for modeling the effect of E/I imbalance on downstream cellular plasticity and oscillatory activity¹. Specifically, they have generated ‘fusion’ organoid structures in which excitatory neuron-predominant cortex (Cx) and inhibitory interneuron-predominant ganglionic eminence (GE) populations are integrated, yielding an ideal platform for modeling E/I balance and its effects on oscillatory activity.

This organoid fusion approach will be used in the current project to model oscillatory activity and cellular changes in the severe neurodevelopmental condition known as developmental epileptic encephalopathy 13 (DEE13). DEE13 is caused by mutations in SCN8A, which encodes the alpha subunit of the voltage-gated sodium channel 1.6 (Na_V1.6). SCN8A is a high-confidence risk gene for ASD. Preliminary results suggest that SCN8A mutant Cx+GE fusion organoids display E/I imbalance and a loss of gamma oscillations consistent with ASD.

The aim of the next set of experiments is to isolate the role of inhibitory versus excitatory neurons in the loss of gamma activity, to identify downstream cell and gene expression changes that result from E/I imbalance, and to test novel therapeutics that can rescue key cellular and physiological phenotypes.