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

다국어 초록 (Multilingual Abstract)

A number of specific genetic variants including gene mutations and single nucleotide variations have been identified in genomewide 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 clearly 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 D2+/- 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.

참고문헌 (Reference)

1 Cooper DN, "Where genotype is not predictive of phenotype : towards an understanding of the molecular basis of reduced penetrance in human inherited disease" 132 : 1077-1130, 2013

2 Gupta VK, "TrkB receptor signalling : implications in neurodegenerative, psychiatric and proliferative disorders" 14 : 10122-10142, 2013

3 Nan X, "Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex" 393 : 386-389, 1998

4 Schmidt MV, "The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse" 21 : 125-132, 2003

5 Merikangas AK, "The phenotypic manifestations of rare genic CNVs in autism spectrum disorder" 20 : 1366-1372, 2015

6 Comings DE, "The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders" 266 : 1793-1800, 1991

7 Chang Q, "The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression" 49 : 341-348, 2006

8 DiCicco-Bloom E, "The developmental neurobiology of autism spectrum disorder" 26 : 6897-6906, 2006

9 Fuccillo MV, "Striatal circuits as a common node for autism pathophysiology" 10 : 27-, 2016

10 이윤진, "Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors" 한국뇌신경과학회 27 (27): 539-549, 2018

11 Dent GW, "Stressinduced alterations in corticotropin-releasing hormone and vasopressin gene expression in the paraventricular nucleus during ontogeny" 71 : 333-342, 2000

12 Sandi C, "Stress and the social brain : behavioural effects and neurobiological mechanisms" 16 : 290-304, 2015

13 Peça J, "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction" 472 : 437-442, 2011

14 Cheng PL, "Self-amplifying autocrine actions of BDNF in axon development" 108 : 18430-18435, 2011

15 Bortolozzi A, "Selective siRNAmediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects" 17 : 612-623, 2012

16 Betancur C, "SHANK3 haploinsufficiency : a"common"but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders" 4 : 17-, 2013

17 Shonesy BC, "Role of striatal direct pathway 2-arachidonoylglycerol signaling in sociability and repetitive behavior" 84 : 304-315, 2018

18 Sim HR, "Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours" 4 : 1579-, 2013

19 Yasuda M, "Robust stimulation of TrkB induces delayed increases in BDNF and Arc mRNA expressions in cultured rat cortical neurons via distinct mechanisms" 103 : 626-636, 2007

20 Shinawi M, "Recurrent reciprocal 16p11. 2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size" 47 : 332-341, 2010

21 Pizzo L, "Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying diseaseassociated variants" 21 : 816-825, 2019

22 Kelly MA, "Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice" 19 : 103-113, 1997

23 김태경, "Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors" 한국뇌신경과학회 25 (25): 163-173, 2016

24 Al Shehhi M, "NRXN1 deletion syndrome;phenotypic and penetrance data from 34 families" 62 : 204-209, 2019

25 Hemmerle AM, "Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation" 168 : 411-420, 2015

26 Mahgoub M, "MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors" 19 : 1506-1512, 2016

27 Hecht PM, "Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress" 9 : 1151-1160, 2016

28 Crafa D, "Maternal migration and autism risk : systematic analysis" 27 : 64-71, 2015

29 Kim H, "Loss of adenylyl cyclase type-5 in the dorsal striatum produces autistic-like behaviors" 54 : 7994-8008, 2017

30 Sampathkumar C, "Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons" 5 : e19374-, 2016

31 Roth TL, "Lasting epigenetic influence of early-life adversity on the BDNF gene" 65 : 760-769, 2009

32 Sjaarda CP, "Interplay between maternal Slc6a4 mutation and prenatal stress : a possible mechanism for autistic behavior development" 7 : 8735-, 2017

33 Boschian C, "Impaired neuronal differentiation of neural stem cells lacking the engrailed-2 gene" 386 : 137-149, 2018

34 Choi J, "Hyperoxygenation revitalizes Alzheimer's disease pathology through the upregulation of neurotrophic factors" 18 : e12888-, 2019

35 Hamdan FF, "High rate of recurrent de novo mutations in developmental and epileptic encephalopathies" 101 : 664-685, 2017

36 Hallmayer J, "Genetic heritability and shared environmental factors among twin pairs with autism" 68 : 1095-1102, 2011

37 English CN, "Genetic evidence that brain-derived neurotrophic factor mediates competitive interactions between individual cortical neurons" 109 : 19456-19461, 2012

38 Deogracias R, "Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome" 109 : 14230-14235, 2012

39 Lai TW, "Excitotoxicity and stroke : identifying novel targets for neuroprotection" 115 : 157-188, 2014

40 Lee Y, "Excessive D1 dopamine receptor activation in the dorsal striatum promotes autistic-like behaviors" 55 : 5658-5671, 2018

41 Koo JW, "Epigenetic basis of opiate suppression of BDNF gene expression in the ventral tegmental area" 18 : 415-422, 2015

42 Grabrucker AM, "Environmental factors in autism" 3 : 118-, 2013

43 Stroud H, "Early-life gene expression in neurons modulates lasting epigenetic states" 171 : 1151.e16-1164.e16, 2017

44 Uchida S, "Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents" 30 : 15007-15018, 2010

45 Chao HT, "Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes" 468 : 263-269, 2010

46 American Psychiatric Association, "Diagnostic and statistical manual of mental disorders" American Psychiatric Publishing 2013

47 D'Angelo D, "Defining the effect of the 16p11. 2 duplication on cognition, behavior, and medical comorbidities" 73 : 20-30, 2016

48 Hamilton PJ, "De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder" 18 : 1315-1323, 2013

49 Staal WG, "DRD3 gene and striatum in autism spectrum disorder" 206 : 431-432, 2015

50 Hettinger JA, "DRD2 and PPP1R1B(DARPP-32)polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families" 8 : 19-, 2012

51 Rice D, "Critical periods of vulnerability for the developing nervous system : evidence from humans and animal models" 108 (108): 511-533, 2000

52 Benthall KN, "Corticostriatal transmission is selectively enhanced in striatonigral neurons with postnatal loss of Tsc1" 23 : 3197-3208, 2018

53 Jones KL, "Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction in mice" 28 : 529-536, 2010

54 백인선, "Chronic Antidepressant Treatment in Normal Mice Induces Anxiety and Impairs Stress-coping Ability" 한국뇌신경과학회 24 (24): 156-168, 2015

55 Bacon C, "Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour" 20 : 632-639, 2015

56 Francis K, "Brain-derived neurotrophic factor(BDNF)in children with ASD and their parents : a 3-year follow-up" 137 : 433-441, 2018

57 Bathina S, "Brain-derived neurotrophic factor and its clinical implications" 11 : 1164-1178, 2015

58 Kang MS, "Autism-like behavior caused by deletion of vacciniarelated kinase 3 is improved by TrkB stimulation" 214 : 2947-2966, 2017

59 Ijichi S, "Autism spectrum disorders: the role of genetics in diagnosis and treatment" InTech 83-102, 2011

60 Singletary WM, "An integrative model of autism spectrum disorder : ASD as a neurobiological disorder of experienced environmental deprivation, early life stress and allostatic overload" 2 : 81-119, 2015

61 Abrahams BS, "Advances in autism genetics : on the threshold of a new neurobiology" 9 : 341-355, 2008

62 Kim H, "Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices" 7 : 77-, 2014

63 Peñagarikano O, "Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits" 147 : 235-246, 2011

64 Jang SW, "A selective TrkB agonist with potent neurotrophic activities by 7, 8-dihydroxyflavone" 107 : 2687-2692, 2010

65 Pavăl D, "A dopamine hypothesis of autism spectrum disorder" 39 : 355-360, 2017

66 Schmid DA, "A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome" 32 : 1803-1810, 2012

67 Hettinger JA, "A DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families" 47B : 628-636, 2008

68 Devi L, "7, 8-dihydroxyflavone, a smallmolecule TrkB agonist, reverses memory deficits and BACE1elevation in a mouse model of Alzheimer's disease" 37 : 434-444, 2012