Synaptic-related developmental dysconnectivity in 22q11.2 deletion syndrome
Poster No:
358
Submission Type:
Abstract Submission
Authors:
Silvia Gini1,2, Filomena Grazia Alvino2, Antea Minetti3, David Sastre-Yagüe1,2, Charles Schleifer4, Alexia Stuefer1,2, Marco Pagani2, Caterina Montani2, Alberto Galbusera2, Francesco Papaleo5, Michael Lombardo6, Massimo Pasqualetti3, Carrie Bearden4, Alessandro Gozzi2
Institutions:
1University of Trento, Rovereto, Italy, 2Istituto Italiano di Tecnologia, Rovereto, Italy, 3University of Pisa, Pisa, Italy, 4University of California at Los Angeles, Los Angeles, CA, 5Istituto Italiano di Tecnologia, Genova, Italy, 6Laboratory for Autism and Neurodevelopmental Disorders, Istituto Italiano di Tecnologia, Rovereto, Italy
First Author:
Co-Author(s):
David Sastre-Yagüe
University of Trento|Istituto Italiano di Tecnologia
Rovereto, Italy|Rovereto, Italy
University of Trento|Istituto Italiano di Tecnologia
Rovereto, Italy|Rovereto, Italy
Michael Lombardo
Laboratory for Autism and Neurodevelopmental Disorders, Istituto Italiano di Tecnologia
Rovereto, Italy
Laboratory for Autism and Neurodevelopmental Disorders, Istituto Italiano di Tecnologia
Rovereto, Italy
Introduction:
22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome characterized by an increased risk of neurodevelopmental disorders including autism and schizophrenia (Gur et al., 2017; Niklasson et al., 2009; Tang et al., 2014). 22q11DS has been consistently linked to alterations in large-scale functional connectivity (Mattiaccio et al., 2016; Scariati et al., 2016). However, the origin and biological determinants of such functional alterations remain largely unexplored. To bridge this knowledge gap, the current study leveraged a cross-species design to track the developmental trajectory of 22q11DS connectopathy and uncover its neurophysiological underpinnings.
Methods:
Mouse studies
We longitudinally mapped resting-state functional connectivity in wildtype (WT, n =22) and LgDel mice (n = 21), an established model of 22q11DS, at two developmental timepoints (juvenile, p33-37; adult, p105-120), using global connectivity (Cole et al., 2010). To assess the biological basis of functional connectivity alterations, we developmentally treated mice with the GSK3β inhibitor SB216763 and longitudinally mapped their functional connectivity (WT SB, n=22; LgDel SB, n=23). Spine density counting in prelimbic cortex and hippocampus was also performed in mice with and without GSK3β inhibition (Juvenile: WT n=4, WT SB n=4, LgDel n=6, LgDel SB n=7; Adult: WT n=4, WT SB n=4, LgDel n=4, LgDel SB n=4).
Human studies
To assess the relevance of our findings for human 22q11DS, we applied the same connectivity mapping methods to individuals with 22q11DS and healthy controls (HC) split into two age subgroups: childhood (6-11 years, 22q11DS n = 21, HC n = 31) and peri/post-puberty (12-30 years, 22q11DS n = 118, HC n = 86). Gene decoding analyses identified genes whose spatial expression matched that of significant age by genotype interaction. Gene enrichment analyses were used to test the overlap between these genes and interactors of GSK3β, or gene lists relevant for neurodevelopmental disorders. The relationship between 22q11DS dysconnectivity and Social Responsiveness Scale scores was assessed using a linear model.
We longitudinally mapped resting-state functional connectivity in wildtype (WT, n =22) and LgDel mice (n = 21), an established model of 22q11DS, at two developmental timepoints (juvenile, p33-37; adult, p105-120), using global connectivity (Cole et al., 2010). To assess the biological basis of functional connectivity alterations, we developmentally treated mice with the GSK3β inhibitor SB216763 and longitudinally mapped their functional connectivity (WT SB, n=22; LgDel SB, n=23). Spine density counting in prelimbic cortex and hippocampus was also performed in mice with and without GSK3β inhibition (Juvenile: WT n=4, WT SB n=4, LgDel n=6, LgDel SB n=7; Adult: WT n=4, WT SB n=4, LgDel n=4, LgDel SB n=4).
Human studies
To assess the relevance of our findings for human 22q11DS, we applied the same connectivity mapping methods to individuals with 22q11DS and healthy controls (HC) split into two age subgroups: childhood (6-11 years, 22q11DS n = 21, HC n = 31) and peri/post-puberty (12-30 years, 22q11DS n = 118, HC n = 86). Gene decoding analyses identified genes whose spatial expression matched that of significant age by genotype interaction. Gene enrichment analyses were used to test the overlap between these genes and interactors of GSK3β, or gene lists relevant for neurodevelopmental disorders. The relationship between 22q11DS dysconnectivity and Social Responsiveness Scale scores was assessed using a linear model.
Results:
fMRI mapping in LgDel mice revealed patterns of age-specific fMRI dysconnectivity. Specifically, we found that widespread fMRI hyperconnectivity in juvenile mice reverted to focal hippocampal hypoconnectivity over puberty (Fig. 1a). Notably, fMRI connectivity changes were mirrored by co-occurring alterations in dendritic spine density (Fig. 1b), suggesting a synaptic origin for this phenomenon. Supporting this notion, we found that both synaptic and fMRI connectivity alterations in juvenile mice were normalized by developmental GSK3β inhibition (Fig. 1c-e). These results suggest that fMRI dysconnectivity in LgDel mice may be related to maladaptive synaptic homeostasis.
In keeping with our mouse results, we identified a similar cortico-hippocampal hyper- to hypoconnectivity reconfiguration over puberty in human 22q11DS (Fig. 2a). Corroborating a synaptic origin of these changes, areas undergoing functional reconfiguration were transcriptionally enriched for synaptic proteins that interact with GSK3β (Fig. 2b, hypergeometric test: OR = 2.91, p= 0.00005). The same regions also exhibited a significant enrichment in autism-related genes (Fig. 2c), suggesting that dysconnectivity in these areas may be relevant to autism-related behavioral traits. In keeping with this notion, developmental dysconnectivity strength was strongly predictive of autism-relevant socio-behavioral symptoms (Fig. 2d).
In keeping with our mouse results, we identified a similar cortico-hippocampal hyper- to hypoconnectivity reconfiguration over puberty in human 22q11DS (Fig. 2a). Corroborating a synaptic origin of these changes, areas undergoing functional reconfiguration were transcriptionally enriched for synaptic proteins that interact with GSK3β (Fig. 2b, hypergeometric test: OR = 2.91, p= 0.00005). The same regions also exhibited a significant enrichment in autism-related genes (Fig. 2c), suggesting that dysconnectivity in these areas may be relevant to autism-related behavioral traits. In keeping with this notion, developmental dysconnectivity strength was strongly predictive of autism-relevant socio-behavioral symptoms (Fig. 2d).
Conclusions:
We document a previously unreported reconfiguration of fMRI dysconnectivity in 22q11DS over puberty. Mouse and human studies converge to suggest that the observed fMRI alterations are underpinned by synaptic-dependent mechanisms, and could be predictive of socio-behavioral alterations. These results shed light on the etiopathological significance and behavioral relevance of fMRI connectivity alterations in 22q11DS.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Psychiatric (eg. Depression, Anxiety, Schizophrenia)
Lifespan Development:
Lifespan Development Other
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Novel Imaging Acquisition Methods:
BOLD fMRI
Keywords:
ANIMAL STUDIES
Autism
Cross-Species Homologues
Development
DISORDERS
FUNCTIONAL MRI
Psychiatric Disorders
Schizophrenia
Other - Synapses
1|2Indicates the priority used for review
Provide references using author date format
Gur, R., Bassett, A., McDonald-McGinn, D., Bearden, C., Chow, E., Emanuel, B., Owen, M., Swillen, A., Van den Bree, M., & Vermeesch, J. (2017). A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11. 2 Deletion Syndrome Brain Behavior Consortium. Molecular Psychiatry, 22(12), 1664-1672.
Mattiaccio, L. M., Coman, I. L., Schreiner, M. J., Antshel, K. M., Fremont, W. P., Bearden, C. E., & Kates, W. R. (2016). Atypical functional connectivity in resting-state networks of individuals with 22q11. 2 deletion syndrome: associations with neurocognitive and psychiatric functioning. Journal of neurodevelopmental disorders, 8(1), 1-14.
Niklasson, L., Rasmussen, P., Óskarsdóttir, S., & Gillberg, C. (2009). Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome. Research in developmental disabilities, 30(4), 763-773.
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