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Early-Life Stress in D2 Heterozygous Mice Promotes Autistic-like Behaviors through the Downregulation of the BDNF-TrkB Pathway in the Dorsal Striatum

Title
Early-Life Stress in D2 Heterozygous Mice Promotes Autistic-like Behaviors through the Downregulation of the BDNF-TrkB Pathway in the Dorsal Striatum
Authors
Lee, YunjinHan, Pyung-Lim
Ewha Authors
한평림
SCOPUS Author ID
한평림scopus
Issue Date
2019
Journal Title
EXPERIMENTAL NEUROBIOLOGY
ISSN
1226-2560JCR Link

2093-8144JCR Link
Citation
EXPERIMENTAL NEUROBIOLOGY vol. 28, no. 3, pp. 337 - 351
Keywords
Autism spectrum disorderearly-life stressdorsal striatumdopamine receptorsTrkB receptor
Publisher
KOREAN SOC BRAIN &

NEURAL SCIENCE, KOREAN SOC NEURODEGENERATIVE DISEASE
Indexed
SCIE; SCOPUS; KCI WOS
Document Type
Article
Abstract
A number of specific genetic variants including gene mutations and single nucleotide variations have been identified in genome-wide association studies of autism spectrum disorder (ASD). ASD phenotypes in individuals carrying specific genetic variations are manifest mostly in a heterozygous state. Furthermore, individuals with most genetic variants show incomplete penetrance and phenotypic variability, suggesting that non-genetic factors are also involved in developing ASD. However, the mechanisms of how genetic and environmental factors interactively promote ASD are not dearly understood. In the present study, we investigated whether early-life stress (ELS) in D2 dopamine receptor heterozygous knockout (D2(+/-)) mice induces ASD-like symptoms. To address that, we exposed D2 heterozygous pups to maternal separation stress for 3 h daily for 13 days beginning on postnatal day 2. D2(+/-) adult mice that had experienced ELS exhibited impaired sociability in the three-chamber test and home-cage social interaction test and increased grooming behavior, whereas wildtype littermates exposed to ELS did not show those phenotypes. ELS-exposed Dr' . mice had decreased levels of BDNF, TrkB,phospho-ERK1/2 and phospho-CREB in the dorsal striatum. Administration of the TrkB agonist 7, 8-dihydroxyflavone (7, 8-DHF) to ELS-exposed D2(+/-) mice rescued the sociability deficits and repetitive behavior. In contrast, behavioral rescue by 7, 8-DHF in ELS-exposed D2(+/-) mice was blocked when TrkB expression in the dorsal striatum was locally inhibited by the injection of TrkB-siRNA. Together, our results suggest that the interaction between ELS and defective D2 gene function promotes autistic-like behaviors by downregulating the BDNF-TrkB pathway in the dorsal striatum.
DOI
10.5607/en.2019.28.3.337
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일반대학원 > 뇌·인지과학과 > Journal papers
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