Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability.
Autism
Intellectual disability
Intracellular signaling
Learning and memory
Sex bias
cAMP
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
02
01
2018
revised:
10
12
2018
accepted:
10
12
2018
pubmed:
9
2
2019
medline:
31
3
2020
entrez:
9
2
2019
Statut:
ppublish
Résumé
The prevalence of neurodevelopmental disorders is biased toward male individuals, with male-to-female ratios of 2:1 in intellectual disability and 4:1 in autism spectrum disorder. However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain-containing protein 1A (CC2D1A), which is mutated in intellectual disability and autism spectrum disorder, we identified biochemical and behavioral differences between male and female mice, and explored whether CC2D1A controls male-specific intracellular signaling. CC2D1A is known to regulate phosphodiesterase 4D (PDE4D), which regulates cyclic adenosine monophosphate (cAMP) signaling. We tested for activation of PDE4D and downstream signaling molecules in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in female mice to analyze learning and memory, and then targeted PDE4D activation with a PDE4D inhibitor to define how changes in cAMP levels affect behavior in male and female mice. We found that in Cc2d1a-deficient male mice PDE4D is hyperactive, leading to a reduction in cAMP response element binding protein signaling, but this molecular deficit is not present in female mice. Cc2d1a-deficient male mice show a deficit in spatial memory, which is not present in Cc2d1a-deficient female mice. Restoring PDE4D activity using an inhibitor rescues cognitive deficits in male mice but has no effect on female mice. Our findings show that CC2D1A regulates cAMP intracellular signaling in a male-specific manner in the hippocampus, leading to male-specific cognitive deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.
Sections du résumé
BACKGROUND
The prevalence of neurodevelopmental disorders is biased toward male individuals, with male-to-female ratios of 2:1 in intellectual disability and 4:1 in autism spectrum disorder. However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain-containing protein 1A (CC2D1A), which is mutated in intellectual disability and autism spectrum disorder, we identified biochemical and behavioral differences between male and female mice, and explored whether CC2D1A controls male-specific intracellular signaling.
METHODS
CC2D1A is known to regulate phosphodiesterase 4D (PDE4D), which regulates cyclic adenosine monophosphate (cAMP) signaling. We tested for activation of PDE4D and downstream signaling molecules in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in female mice to analyze learning and memory, and then targeted PDE4D activation with a PDE4D inhibitor to define how changes in cAMP levels affect behavior in male and female mice.
RESULTS
We found that in Cc2d1a-deficient male mice PDE4D is hyperactive, leading to a reduction in cAMP response element binding protein signaling, but this molecular deficit is not present in female mice. Cc2d1a-deficient male mice show a deficit in spatial memory, which is not present in Cc2d1a-deficient female mice. Restoring PDE4D activity using an inhibitor rescues cognitive deficits in male mice but has no effect on female mice.
CONCLUSIONS
Our findings show that CC2D1A regulates cAMP intracellular signaling in a male-specific manner in the hippocampus, leading to male-specific cognitive deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.
Identifiants
pubmed: 30732858
pii: S0006-3223(18)32098-5
doi: 10.1016/j.biopsych.2018.12.013
pmc: PMC6474812
mid: NIHMS1520758
pii:
doi:
Substances chimiques
Freud-1 protein, mouse
0
Repressor Proteins
0
Cyclic AMP
E0399OZS9N
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
760-768Subventions
Organisme : NCRR NIH HHS
ID : U42 RR024244
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090257
Pays : United States
Organisme : NICHD NIH HHS
ID : P30 HD040677
Pays : United States
Organisme : NICHD NIH HHS
ID : R00 HD067379
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004080
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001876
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105000
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004085
Pays : United States
Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Références
Neurosci Lett. 2010 Oct 11;483(2):148-51
pubmed: 20691760
Clin Epidemiol. 2014 Jan 08;6:37-48
pubmed: 24470773
Cell Rep. 2014 Aug 7;8(3):647-55
pubmed: 25066123
Front Genet. 2018 Mar 02;9:65
pubmed: 29552027
Br J Pharmacol. 2011 Dec;164(8):2054-63
pubmed: 21649644
Neurotherapeutics. 2015 Jan;12(1):29-41
pubmed: 25575647
Behav Neurosci. 1998 Feb;112(1):141-53
pubmed: 9517822
Neurotherapeutics. 2015 Jan;12(1):49-56
pubmed: 25371167
Metab Brain Dis. 2016 Jun;31(3):613-9
pubmed: 26782176
Neuron. 2011 Jun 9;70(5):898-907
pubmed: 21658583
Brain Res. 2006 Jun 22;1096(1):104-12
pubmed: 16730340
Mol Psychiatry. 2015 Mar;20(3):369-76
pubmed: 24888361
Horm Behav. 2009 Aug;56(2):199-205
pubmed: 19406124
J Neurosci. 2017 Dec 6;37(49):11967-11978
pubmed: 29101244
Philos Trans R Soc Lond B Biol Sci. 2016 Feb 19;371(1688):20150111
pubmed: 26833832
J Clin Psychiatry. 2005;66 Suppl 10:3-8
pubmed: 16401144
Nat Protoc. 2006;1(2):848-58
pubmed: 17406317
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5258-62
pubmed: 23431162
J Neurosci Methods. 1984 May;11(1):47-60
pubmed: 6471907
Cell Commun Signal. 2013 Jul 04;11(1):47
pubmed: 23826796
Nat Neurosci. 2002 Apr;5(4):348-55
pubmed: 11889468
Learn Mem. 2015 Aug 18;22(9):472-93
pubmed: 26286657
J Neurosci. 2003 Aug 13;23(19):7415-25
pubmed: 12917378
Neuropsychopharmacology. 2002 Oct;27(4):587-95
pubmed: 12377395
J Biol Chem. 2012 Apr 27;287(18):14644-58
pubmed: 22375002
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13217-21
pubmed: 12244210
JAMA Psychiatry. 2017 Mar 1;74(3):293-299
pubmed: 28097321
Nat Med. 2017 Sep;23(9):1102-1111
pubmed: 28825715
Neuropsychopharmacology. 2017 Jan;42(2):397-407
pubmed: 27577601
Behav Brain Res. 1993 Oct 21;57(1):47-51
pubmed: 8292254
PLoS Genet. 2015 Dec 31;11(12):e1005749
pubmed: 26720614
Cereb Cortex. 2017 Feb 1;27(2):1670-1685
pubmed: 26826102
Neuropharmacology. 2014 Feb;77:120-30
pubmed: 24067928
Learn Mem. 2009 Feb 23;16(3):198-209
pubmed: 19237642
Dev Cell. 2006 Nov;11(5):655-69
pubmed: 17084358
Exp Mol Med. 2014 May 02;46:e93
pubmed: 24787734
J Neurophysiol. 2011 Apr;105(4):1506-15
pubmed: 21273312
Mol Psychiatry. 2018 Mar;23(3):544-555
pubmed: 29038598
Int J Neuropsychopharmacol. 2010 Sep;13(8):1089-101
pubmed: 20392296
PLoS One. 2009;4(5):e5464
pubmed: 19421325
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):4868-9
pubmed: 23476067
Genome Med. 2016 Nov 1;8(1):105
pubmed: 27799067
Cell. 2002 Mar 8;108(5):689-703
pubmed: 11893339
J Med Genet. 2006 Mar;43(3):203-10
pubmed: 16033914
PLoS Biol. 2011 Jun;9(6):e1001081
pubmed: 21695109
MMWR Surveill Summ. 2018 Apr 27;67(6):1-23
pubmed: 29701730
J Biol Chem. 2012 Sep 14;287(38):32216-21
pubmed: 22833682
JAMA Psychiatry. 2016 Jun 1;73(6):614-21
pubmed: 27096285
Cell. 1996 Dec 27;87(7):1317-26
pubmed: 8980237
Mamm Genome. 1997 Oct;8(10):711-3
pubmed: 9321461
Dev Cell. 2006 Nov;11(5):641-53
pubmed: 17084357
J Neurosci. 2005 May 18;25(20):5066-78
pubmed: 15901789
Cell. 1994 Oct 7;79(1):59-68
pubmed: 7923378
Dialogues Clin Neurosci. 2016 Dec;18(4):361-372
pubmed: 28179808
Oncogene. 2003 May 22;22(21):3307-18
pubmed: 12761501
Br J Pharmacol. 2015 Oct;172(20):4785-9
pubmed: 26211680