PREFRONTAL CORTEX CONTRIBUTIONS TO CHARGE SYNDROME: FROM SYNAPSES TO BEHAVIOUR

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a substantial personal and societal burden, yet effective interventions for its core symptoms remain elusive. Although hundreds of ASD risk genes have been identified, how different mutations converge to produce common behavioural and cognitive phenotypes is unclear. Several high-confidence ASD risk genes are linked to transcriptional regulation, including the chromatin remodeller CHD7. Pathogenic variants in CHD7 cause CHARGE syndrome (CS), a rare but severe multisystem disorder associated with intellectual disability, executive dysfunction, and ASD. Previous studies have reported reduced white matter volume and brain hypoplasia, including the prefrontal cortex (PFC), in mutant mice, but circuit abnormalities that may underlie some of the symptoms associated with CS have not been addressed.
Here, we provide the first evidence that Chd7 haploinsufficiency disrupts PFC function during postnatal development by using a heterozygous gene-trap mouse line and a combination of electrophysiological, behavioural and imaging approaches.
We observed increased impulsivity and impaired social interactions at postnatal days 14-15 (P14-15), and male-specific deficits in maternal discrimination at P20-21. Electrophysiological recordings revealed altered excitatory synaptic transmission and increased neuronal excitability in PFC layer 5 pyramidal neurons, corroborated by heightened cFos expression at P14-15, with some sex specific changes.
Together, these findings identify a temporal window during which Chd7 haploinsufficiency perturbs PFC circuitry and behaviour, implicating excitation/inhibition imbalance in the PFC as a mechanistic link between gene dysfunction and neurodevelopmental phenotypes. Our results provide insight into a developmental window during which therapeutic intervention might be most effective.