Journal article
Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders
Molecular psychiatry, Vol.23(3), pp.544-555
2018
DOI: 10.1038/mp.2017.184
PMID: 29038598
Abstract
Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.
Details
- Title: Subtitle
- Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders
- Creators
- N M Grissom - Institute for Translational Medicine and Therapeutics, University of PennsylvaniaS E McKee - Institute for Translational Medicine and Therapeutics, University of PennsylvaniaH Schoch - Department of Biology, University of PennsylvaniaN Bowman - Department of Neuroscience, University of PennsylvaniaR Havekes - Department of Biology, University of PennsylvaniaW T O'Brien - Department of Neuroscience, University of PennsylvaniaE Mahrt - School of Biological Sciences, Washington State University VancouverS Siegel - Department of Psychiatry, University of PennsylvaniaK Commons - Department of Anesthesia, Boston Children’s Hospital, Harvard Medical SchoolC Portfors - School of Biological Sciences, Washington State University VancouverT Nickl-Jockschat - Jülich Aachen Research Alliance—Translational Brain MedicineT M Reyes - Institute for Translational Medicine and Therapeutics, University of PennsylvaniaT Abel - Department of Biology, University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.23(3), pp.544-555
- DOI
- 10.1038/mp.2017.184
- PMID
- 29038598
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Publisher
- Nature Publishing Group
- Alternative title
- Male-specific deficits in a mouse model of 16p11.2 hemideletion
- Language
- English
- Date published
- 2018
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984003965802771
Metrics
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