Role of GABA interneurons in a genetic model of autism

Rett syndrome involves a number of developmental deficits similar to those observed in autism, including dysregulated motor movements, communication skills and cognitive processes. Rett syndrome is caused by mutations in a single gene, MeCP2, allowing researchers to study the disorder in mice that carry the mutations.

Jessica Cardin and her colleagues at Yale University plan to use recordings of brain activity in Rett model mice to better understand how genetic alterations in specific cells lead to impaired brain function.

MeCP2 is strongly expressed in inhibitory interneurons, a diverse population of specialized cells that use the neurotransmitter GABA to communicate with other neurons. Under healthy conditions, inhibitory interneurons regulate the activity of brain networks, maintaining stable conditions for cognition and perception. Selective deletion of MeCP2 from these cells replicates many of the characteristics of Rett syndrome, suggesting that GABA-related dysfunction plays a major role in the disease.

GABAergic deficits have also been implicated in autism. However, the contributions of distinct inhibitory cell types to disease-related neural deficits remain unknown. Cardin’s group plans to address this question by generating mice in which the MeCP2 gene is selectively deleted from individual groups of inhibitory cells, and then recording the brain activity of each mouse line.

The researchers plan to use electrophysiology and optogenetics to assay the activity and impact of specific classes of inhibitory interneurons in the primary visual cortex that lack MeCP2. Basic neural functions associated with GABAergic activity in this area include visual response properties and gamma oscillations.

MeCP2 deletion is known to dysregulate the formation and function of synapses, the junctions between neurons, but the cell-type-specific role of MeCP2 in these processes is unclear. Cardin and her colleagues plan to use intracellular recordings from excitatory pyramidal neurons of the visual cortex to measure synaptic activity in mice while they are awake. This would enable them to explore the role of interneuron MeCP2 expression in maintaining stable brain activity.