Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

• Published in: Translational psychiatry Vol. 11; no. 1; p. 181
• Main Authors: Lichtman, Daniela, Bergmann, Eyal, Kavushansky, Alexandra, Cohen, Nadav, Levy, Nina S., Levy, Andrew P., Kahn, Itamar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-03-2021; Nature Publishing Group
• Subjects: 59/36; 64/110; 64/60; 692/53/2421; 692/699/476/1373; Animals; Autism; Autism Spectrum Disorder - diagnostic imaging; Autism Spectrum Disorder - genetics; Autistic Disorder - diagnostic imaging; Autistic Disorder - genetics; Behavioral Sciences; Biological Psychology; Brain - diagnostic imaging; Brain - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Magnetic Resonance Imaging; Medicine; Medicine & Public Health; Mice; Mutation; Nerve Tissue Proteins; Neurosciences; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-021-01289-8

IQSEC2
is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of
IQSEC2
(A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to
IQSEC2
mutations.