New approaches to dissect neuronal circuits dynamics in ASD

Many autism spectrum disorder (ASD) models exhibit disruptions in functional connectivity across both short- and long-range brain circuits.

However, the wiring and function of callosal projection neurons (CPN)—key cells responsible for connecting the two hemispheres of the brain—have remained largely unexplored, especially in relation to cognitive abilities and flexibility.

The Fagiolini lab has been investigating CDKL5 Deficiency Disorder, a severe ASD subtype caused by mutations in the CDKL5 gene on the X chromosome, which is known for causing cognitive impairments and early-onset epilepsy.

In a recent publication, the Dr. Fagiolini's team demonstrated that the CDKL5 gene plays a crucial role in shaping appropriate callosal connectivity, which in turn underlies cognitive flexibility. Their findings establish a direct relationship between dysfunction in CPNs and cognitive deficits in a neurodevelopmental disorder model. Ongoing studies are now investigating how manipulating CDKL5 expression on either side of the synapse affects CPN connections.

These foundational results are enabling new collaborative projects focused on understanding how callosal connectivity affects visual processing in health and ASD, and on designing targeted interventions to restore normal circuit function.