Autism spectrum disorder (ASD) is often linked to mutations in genes regulating synaptic development and mRNA translation, implicating synaptic connectivity in its pathogenesis. Research indicates that synaptic deficits in ASD are cell type-specific, particularly affecting the balance between excitatory and inhibitory (E/I) neurotransmission in cortical circuits. Disruptions in E/I balance are associated with ASD comorbidities such as epilepsy. Funded by a SFARI Pilot Award, Beatriz Rico and Oscar Marin revealed that excitatory synapses on parvalbumin-expressing (PV+) interneurons are particularly sensitive to local protein synthesis disruptions. Specifically, in mice, the deletion of Tsc2, a negative regulator of the mTOR signaling pathway, abnormally increases the connectivity between pyramidal cells and PV+ interneurons.
In this project, Rico and her colleagues propose to investigate whether alterations in other critical regulators of the mTOR pathway have a similar effect on the maturation and wiring of cortical PV+ interneurons in mice. By examining cortical tissue from patients with mTOR-related conditions, they also aim to understand the translational potential of their findings. Finally, Rico’s team plans to perform experimental manipulations in human organotypic slice cultures, obtained from surgical resections, to determine whether genes coding for proteins regulating the mTOR signaling pathway, whose mutation is associated with epilepsy and ASD, affect the wiring of human PV+ interneurons in a cell-autonomous manner. This research will increase the understanding of the molecular mechanisms underpinning mTORpathies, a spectrum of syndromes frequently associated with epilepsy and ASD.