Neuropsychiatric disorders, such as schizophrenia and autism, are highly heritable, polygenic diseases. Thus, delineating polygenic contributions that increase vulnerability and identifying their impact on the brain is a key requirement to understand the molecular mechanisms underlying psychiatric disorders. As copy number variations (CNVs) - large deletions or duplications of DNA - span over multiple genes and show high penetrance, they are ideal candidates to study these mechanisms. Our panel will present different approaches in this field that span rodent and human work.
Alessandro Gozzi will present mouse resting-state fMRI studies to deconstruct the heterogeneous expression of functional connectivity in autism spectrum disorders (ASD) by imaging multiple genetic models and by linking mechanistic pathways to specific connectional fingerprints in human populations. This work indicates that autism-related mutations alter brain-wide oscillatory fMRI network dynamics.
Andreas Meyer-Lindenberg will present profiles of brain connectivity and morphology alterations in 22q11.2, 15q13.3 and 1q21.1 CNV mouse lines and delineated systems-level brain changes, which could provide a translational endophenotype for understanding the pathophysiological mechanisms behind the liability to neuropsychiatric traits associated with these deletions..
Thomas Nickl-Jockschat will present results derived from novel approaches linking changes of brain structure and function to spatial gene expression patterns in different mouse models of CNVs associated with schizophrenia and autism. These tools allow to form data-driven hypotheses about molecular underpinnings that can be later tested in the wet lab.
Bogdan Draganski will present multi-parameter human MRI findings in 16p11 and 1q21 deletion and duplication carriers to show their impact on gradients of iron distribution and link these to behavioural phenotypes. This approach allows inference on microstructural changes in human carriers.
Distinct systems-level mechanisms for CNV variants associated with schizophrenia and autism – evidence from translational neuroimaging
Andreas Meyer-Lindenberg, Mannheim (Germany)
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Andreas Meyer-Lindenberg, Mannheim (Germany)
22q11.2, 15q13.3 and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia, autism and mental retardation. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. A fundamental open question is whether convergent neural mechanisms mediate this genetic pleiotropic association with the same behavioral phenotypes. Here, we use a combination of rodent microdeletion models with high-field neuroimaging to perform a comparative whole-brain characterization of functional and structural mechanisms linked to high-risk states. We found that the three microdeletions did not share significant systems-level features. Instead, morphometric analyses revealed microcephaly in 1q21.1 and macrocephaly in 15q13.3 deletions. In function, 22q11.2 deletion mice showed wide-spread cortical hypoconnectivity, accompanied by opposing hyperconnectivity in dopaminergic pathways. Graph analysis confirmed these results by revealing a differential embedding of dopaminergic regions into brain topology. The other two groups did not show this abnormality, but exhibited changes in midbrain connectivity in 1q21.1 and auditory/striatal system in 15q13.3. The combination of cortical hypoconnectivity and dopaminergic hyperconnectivity in 22q11.2 deletion mirrors key neurodevelopmental features of schizophrenia, while changes in the midbrain and auditory/striatal topology in 1q21.1 and 15q13.3 rather indicate focal processes possibly linked to the emergence of abnormal salience perception and hallucinations. In addition to insights into pathophysiological processes in these specific microdeletions, our results establish the general point that microdeletions increase risk for overlapping sets of neuropsychiatric phenotypes through separable neural mechanisms.
Mapping the connectional landscape in autism with cross-species fMRI
Alessandro Gozzi, Rovereto (Italy)
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Alessandro Gozzi, Rovereto (Italy)
Prominent and yet highly heterogeneous abnormalities in interregional connectivity characterize autism. However, several fundamental questions as to the origin of this phenomenon remain unaddressed. For one, does etiopathological variability account for heterogeneous connectivity in autism? And can we link autism-associated genetic alterations to specific patterns of functional disconnectivity? To address these questions, we have developed fMRI-based methods for connectivity mapping in the laboratory mouse, where specific autism-related etiologies can be isolated and investigated with high precision. We observed significant mouse to human correspondences in network organization, and conserved patterns of disconnectivity in rodents and humans harboring autism-associated 16p11.2 chromosome microdeletion. By extending this approach to multiple autism risk genes, we then showed that different genetic etiologies lead to a spectrum of heterogeneous, yet classifiable cross-mutational connectivity fingerprints, that are associated with disrupted network dynamics. Our results establish a mechanistic link between neuro-genetic abnormalities, specific patterns of disconnectivity and their heterogeneous expression across clinical populations.