Developmental E/I imbalance leads to fMRI hypoconnectivity via transcriptional dysregulation
Poster No:
266
Submission Type:
Abstract Submission
Authors:
Alexia Stuefer1, Giulia Colombo2, Silvia Gini1, David Sastre-Yague1, Ludovico Coletta3, Federico Rocchi1, Marco Aldrighetti1, Bianca D’Epifanio1, Gianluca Como2, Luigi Balasco4, Noemi Barsotti5, Caterina Montani6, Filomena Alvino1, Alberto Galbusera1, Sine Bertozzi2, Francesco Papaleo2, Giuliano Iurilli1, Massimo Pasqualetti5, Yuri Bozzi7, Valter Tucci2, Laura Cancedda2, Michael Lombardo1, Alessandro Gozzi1
Institutions:
1Istituto Italiano di Tecnologia, Rovereto, Trento, 2Istituto Italiano di Tecnologia, Genova, Genova, 3Fondazione Bruno Kessler, Trento, Trento, 4University of Trento, Trento, Trento, 5University of Pisa, Pisa, Pisa, 6IRCCS Ospedale Policlinico San Martino, Genova, Genova, 7University of Trento, Rovereto, Trento
First Author:
Co-Author(s):
Introduction:
Altered functional connectivity is a hallmark-finding in autism and related neurodevelopmental disorders (Geschwind, 2009; Vasa et al., 2016; Bertero et al., 2018; Pagani et al., 2019; Pagani et al., 2021). However, the developmental mechanism leading to these alterations remains unclear. A popular theory posits that an imbalance between excitation and inhibition (E/I) might contribute to the etiology of developmental disorders (Rubenstein and Merzenich, 2003). This raises the intriguing possibility that altered functional connectivity may reflect developmental alterations produced by transient postnatal E/I imbalance. To test this hypothesis, here we transiently alter E/I balance in the neocortex of the mouse brain using chemogenetics, and longitudinally measure the behavioral, neuroimaging and transcriptional phenotypes produced by this manipulation.
Methods:
Cell-type specific increase of neuronal excitability was obtained using intersectional genetics and chemogenetics. Specifically, we expressed the excitatory DREADD receptor hM3Dq in Vglut1-cre mice. Upon chronic CNO treatment during the first two postnatal weeks, this preparation induced cell-type specific increase of neuronal excitability (Control N = 29, Vglut1-gq N = 27, mixed sexes). Following CNO treatment we carried out longitudinal resting state fMRI, behavioral tests, and RNA-sequencing and electrophysiological measurements (in slice patch clamp as well as EEG recordings) were performed at multiple developmental stages (late infancy, adolescence and adulthood).
Results:
We found that developmental E/I imbalance in the mouse neocortex triggers a cascade of lasting changes that affect both behaviour and functional organization of large-scale connectivity. Specifically, we found that early increase in neocortical excitability permanently disrupted functional connectivity, particularly within the fronto-hippocampal regions of the social brain, while sensory networks remain unaffected. This disruption was associated with impaired sociability, whereas cognitive and motor-sensory functions appear largely intact. Interestingly, when we applied the same manipulation to adolescent mice, we observed no changes, emphasizing the developmental specificity of these effects.
Using RNA-sequencing, we found that perinatal E/I imbalance led to transcriptional dysregulation of autism-risk and synaptic genes, suggesting the involvement of activity-dependent transcriptional mechanisms. These changes were associated with altered maturation of pyramidal neurons, generating lasting population level hyperexcitability in adulthood as probed with EEG. Through gene decoding and enrichment analysis, we confirmed that genes most affected by early excitation are predominantly expressed in hypo-connected social brain areas, thus suggesting the observed connectivity alteration may reflect activity-dependent epigenetic changes in the manipulated neurons. Finally, we found that hypoconnectivity between prefrontal regions and dopaminergic nuclei strongly predicted social deficits, highlighting the behavioural significance of these findings.
Using RNA-sequencing, we found that perinatal E/I imbalance led to transcriptional dysregulation of autism-risk and synaptic genes, suggesting the involvement of activity-dependent transcriptional mechanisms. These changes were associated with altered maturation of pyramidal neurons, generating lasting population level hyperexcitability in adulthood as probed with EEG. Through gene decoding and enrichment analysis, we confirmed that genes most affected by early excitation are predominantly expressed in hypo-connected social brain areas, thus suggesting the observed connectivity alteration may reflect activity-dependent epigenetic changes in the manipulated neurons. Finally, we found that hypoconnectivity between prefrontal regions and dopaminergic nuclei strongly predicted social deficits, highlighting the behavioural significance of these findings.
·Figure 1 Developmental E/I imbalance permanently disrupts functional connectivity in a circuit-specific manner.
·Figure 2 E/I imbalance in early development causes transcriptional dysregulation of autism-risk and synaptic genes.
Conclusions:
Early developmental insults can disrupt the normal trajectory of brain maturation, impairing the formation and function of neural circuits. Our findings suggest that such disruptions may arise from alterations in E/I balance during critical periods of development. Specifically, early hyperexcitability can induce epigenetic changes in activity-dependent gene expression in a circuit-specific manner. These changes lead to abnormal electrical properties, disrupted functional coupling, and behavioral alterations associated with these circuits. This study highlights a potential mechanism underlying the hypoconnectivity observed in neurodevelopmental disorders.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Emotion, Motivation and Social Neuroscience:
Social Neuroscience Other
Genetics:
Transcriptomics
Lifespan Development:
Early life, Adolescence, Aging
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Keywords:
ANIMAL STUDIES
Autism
Development
DISORDERS
FUNCTIONAL MRI
MRI
Neuron
Psychiatric Disorders
Social Interactions
Other - Excitation/inhibition imbalance
1|2Indicates the priority used for review
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Provide references using APA citation style.
Geschwind D.H. (2009) Advances in autism. Annu Rev Med 60:367-380.
Pagani M. (2019) Deletion of autism risk gene Shank3 disrupts prefrontal connectivity. The Journal of Neuroscience:2529-2518.
Pagani M. (2021) mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity. Nature Communications 12:6084.
Rubenstein J.L. (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255-267.
Vasa R.A. (2016) The Disrupted Connectivity Hypothesis of Autism Spectrum Disorders: Time for the Next Phase in Research. Biol Psychiatry Cogn Neurosci Neuroimaging 1:245-252.