Upcoming Sminars

Abstract

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for developmental disorders, including autism and schizophrenia. Brain imaging studies have reported atypical large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3β inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper- to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3β, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

Biosketch

Filomena Grazia Alvino earned her PhD in Behavioral Neuroscience from Sapienza University of Rome in 2018 under the supervision of Dr. Elvira De Leonibus (CNR, Naples), where she conducted studies on the neural basis of memory capacity in rodents. She then joined as a post-doctoral fellow in the Gozzi laboratory at the Istituto Italiano di Tecnologia (IIT) in Rovereto. Her current research focuses on the use of cross-species approaches to study the neural basis of fMRI connectivity alterations in neurodevelopmental disorders such as autism and schizophrenia. Her work has revealed analogous connectivity alterations in a mouse model and humans with 22q11.2 deletion syndrome, a highly penetrant cause of such disorders. These alterations are caused by an aberrant synaptic phenotype across development in mice with the deletion, and they are correlated with expression patterns of synaptic genes in human carriers.