Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

Timothy P. Rutkowski, Ryan H. Purcell, Rebecca M. Pollak, Stephanie M. Grewenow, Georgette M. Gafford, Tamika Malone, Uswa A. Khan, Jason P. Schroeder, Michael P. Epstein, Gary J. Bassell, Stephen T. Warren, David Weinshenker, Tamara Caspary, Jennifer Gladys Mulle

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. In addition, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/- mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.

Original languageEnglish
Pages (from-to)772-783
Number of pages12
JournalMolecular Psychiatry
Volume26
Issue number3
DOIs
StatePublished - Mar 2021
Externally publishedYes

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