Abstract
Although autism spectrum disorders (ASDs) share a core set of nosological features, they exhibit substantial genetic heterogeneity. A parsimonious hypothesis posits that dysregulated epigenetic mechanisms represent common pathways in the etiology of ASDs. To investigate this hypothesis, we generated a novel mouse model resulting from brain-specific deletion of chromodomain helicase DNA-binding 5 (Chd5), a chromatin remodeling protein known to regulate neuronal differentiation and a member of a gene family strongly implicated in ASDs. RNA sequencing of Chd5− / − mouse forebrain tissue revealed a preponderance of changes in expression of genes important in cellular development and signaling, sociocommunicative behavior and ASDs. Pyramidal neurons cultured from Chd5− / − cortex displayed alterations in dendritic morphology. Paralleling ASD nosology, Chd5− / − mice exhibited abnormal sociocommunicative behavior and a strong preference for familiarity. Chd5− / − mice further showed deficits in responding to the distress of a conspecific, a mouse homolog of empathy. Thus, dysregulated chromatin remodeling produces a pattern of transcriptional, neuronal and behavioral effects consistent with the presentation of ASDs.
Original language | English (US) |
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Article number | e1152 |
Journal | Translational psychiatry |
Volume | 7 |
Issue number | 6 |
DOIs | |
State | Published - 2017 |
Bibliographical note
Funding Information:This research is supported by the Autism Initiative (University of Minnesota), the Gralnick Prize for Research on Severe Mental Disorders (American Psychological Foundation), Lieber Prize for Outstanding Schizophrenia Research (NARSAD), University of Louisville Grawemeyer Prize in Psychology, and University of Minnesota’s Center for Cognitive Sciences (5T32HD007151). We thank Britta Logdahl, Ruby Ouloch and Zofeyah McBrayer for assistance with data collection, Lorene Lanier and Thomas Bastian for guidance with cell-culturing experiments; Jon Vettervall and Robert Klink for PCR assistance; Emily Leathley Wozniak for western blot assistance; Michael Pazin for Chd5 protein antibodies; Michael Saxe and Yan-Ping Zhang for ultrasonic vocalization analysis code; Phu Tran for RNA-seq analysis assistance; and David Largespada for nestin-Cre transgenic mice. We also wish to express our humble gratitude to Irv Gottesman, our co-author and colleague, who passed away during the preparation of this manuscript.
Publisher Copyright:
© The Author(s) 2017.