title: MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease.
abstract: Major histocompatibility complex class I (MHCI) molecules negatively regulate cortical connections and are implicated in neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. However, the mechanisms that mediate these effects are unknown. Here, we report a novel MHCI signaling pathway that requires the myocyte enhancer factor 2 (MEF2) transcription factors. In young rat cortical neurons, MHCI regulates MEF2 in an activity-dependent manner and requires calcineurin-mediated activation of MEF2 to limit synapse density. Manipulating MEF2 alone alters synaptic strength and GluA1 content, but not synapse density, implicating activity-dependent MEF2 activation as critical for MHCI signaling. The MHCI-MEF2 pathway identified here also mediates the effects of a mouse model of maternal immune activation (MIA) on connectivity in offspring. MHCI and MEF2 levels are higher, and synapse density is lower, on neurons from MIA offspring. Most important, dysregulation of MHCI and MEF2 is required for the MIA-induced reduction in neural connectivity. These results identify a previously unknown MHCI-calcineurin-MEF2 signaling pathway that regulates the establishment of cortical connections and mediates synaptic defects caused by MIA, a risk factor for autism spectrum disorders and schizophrenia.
authors: Center for Neuroscience, University of California, Davis, CA 95618, USA.
authors: Bradford M
authors: BM
authors: Elmer
authors: Myka L
authors: ML
authors: Estes
authors: Stephanie L
authors: SL
authors: Barrow
authors: A Kimberley
authors: AK
authors: McAllister
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009778:Occipital Lobe / Q000166:cytology; D011070:Poly I-C / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000276:immunology; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D015395:Histocompatibility Antigens Class I; D064326:MEF2 Transcription Factors; D008869:Microtubule-Associated Proteins; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D019703:Calcineurin; D011070:Poly I-C
references: Nat Protoc. 2006;1(3):1287-96
references: 17406413
references: Science. 2006 Feb 17;311(5763):1008-12
references: 16484497
references: J Neurosci Methods. 2008 Jun 30;171(2):239-47
references: 18471889
references: Neuron. 2012 Mar 22;73(6):1100-7
references: 22445338
references: Neuropsychopharmacology. 2008 Jan;33(2):441-56
references: 17443130
references: Neuron. 2010 Apr 29;66(2):191-7
references: 20434996
references: PLoS One. 2009 Dec 29;4(12):e8472
references: 20041152
references: Biol Psychiatry. 2010 Oct 1;68(7):671-3
references: 20673877
references: Pediatrics. 2012 Dec;130(6):e1447-54
references: 23147969
references: Science. 2013 Mar 1;339(6123):1095-9
references: 23449593
references: EMBO J. 2009 Mar 18;28(6):697-710
references: 19197241
references: Schizophr Bull. 2011 Mar;37(2):284-90
references: 21134972
references: Nature. 2012 Apr 04;485(7397):242-5
references: 22495311
references: Nature. 2009 Aug 6;460(7256):744-7
references: 19571808
references: Brain Behav Immun. 2013 Jul;31:54-68
references: 22841693
references: J Immunol. 1995 Feb 1;154(3):1167-76
references: 7529791
references: Trends Neurosci. 2007 Mar;30(3):126-34
references: 17275103
references: Science. 2008 May 30;320(5880):1224-9
references: 18511691
references: Neurosci Biobehav Rev. 2009 Jul;33(7):1061-79
references: 19442688
references: J Immunol. 1997 Apr 1;158(7):3189-96
references: 9120273
references: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6784-9
references: 19346486
references: Mol Cell Neurosci. 2010 May;44(1):94-108
references: 20197093
references: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22278-83
references: 21135233
references: Clin Genet. 2010 Nov;78(5):471-7
references: 20412115
references: Science. 2006 Sep 22;313(5794):1795-800
references: 16917027
references: Nat Neurosci. 2012 Sep;15(9):1255-64
references: 22885849
references: J Neuroinflammation. 2012 Apr 30;9:83
references: 22546005
references: Trends Neurosci. 2012 Nov;35(11):660-70
references: 22939644
references: Neuron. 2008 Aug 28;59(4):621-33
references: 18760698
references: Behav Brain Funct. 2011 Jan 04;7:1
references: 21205317
references: Brain Behav Immun. 2012 May;26(4):607-16
references: 22310922
references: Cell Tissue Res. 2013 May;352(2):179-90
references: 23397426
references: J Neurosci. 2012 Sep 12;32(37):12780-5
references: 22973001
references: PLoS One. 2011 Mar 31;6(3):e18439
references: 21483793
references: J Neurosci. 2003 Jan 1;23(1):297-302
references: 12514227
references: J Neuroimmunol. 2011 Mar;232(1-2):8-16
references: 20950866
references: Cell. 2012 Sep 28;151(1):41-55
references: 23021214
references: Am J Med Genet A. 2011 Oct;155A(10):2386-96
references: 22031302
references: J Neurosci. 2006 May 3;26(18):4752-62
references: 16672647
references: Neuron. 1998 Sep;21(3):505-20
references: 9768838
references: Science. 2000 Dec 15;290(5499):2155-9
references: 11118151
references: Neuron. 2010 Nov 18;68(4):639-53
references: 21092855
references: J Neuroimmunol. 2012 Jun 15;247(1-2):1-8
references: 22503373
references: Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6828-33
references: 17420446
references: Annu Rev Neurosci. 2002;25:103-26
references: 12052905
references: Science. 2006 Feb 17;311(5763):1012-7
references: 16484498
references: J Biol Chem. 2000 Jan 7;275(1):197-209
references: 10617605
references: Science. 1999 Oct 22;286(5440):785-90
references: 10531066
references: J Neurosci. 2010 Jan 27;30(4):1270-87
references: 20107055
references: J Neurosci. 2003 Aug 13;23(19):7326-36
references: 12917366
references: Hum Immunol. 1989 Aug;25(4):269-89
references: 2475477
references: Dev Neurobiol. 2012 Oct;72(10):1288-301
references: 22760919
references: APMIS. 1999 Oct;107(10):887-95
references: 10549585
references: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9391-6
references: 18599438
references: Schizophr Res. 2008 Feb;99(1-3):56-70
references: 18248790
references: Curr Top Dev Biol. 2005;69:239-66
references: 16243602
references: J Neurosci. 1995 Aug;15(8):5727-38
references: 7643214
references: Int J Dev Neurosci. 2005 Apr-May;23(2-3):299-305
references: 15749254
references: Cell Immunol. 1990 Mar;126(1):196-210
references: 2137376
references: Brain Behav Immun. 2010 Aug;24(6):930-41
references: 20227486
references: Mol Cell Neurosci. 2013 Jan;52:117-27
references: 23147111
references: PLoS Genet. 2013 Apr;9(4):e1003455
references: 23637625
references: J Immunol. 2003 Feb 15;170(4):1894-902
references: 12574356
references: J Neurosci. 2013 Mar 13;33(11):4726-40
references: 23486945
references: Pediatr Res. 2011 May;69(5 Pt 2):26R-33R
references: 21289540
references: Nature. 2009 Aug 6;460(7256):748-52
references: 19571811
references: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7561-6
references: 10852968
references: Development. 2007 Dec;134(23):4131-40
references: 17959722
references: Nature. 2009 Aug 6;460(7256):753-7
references: 19571809
references: Autism Res Treat. 2012;2012:959073
references: 22928105
references: Biol Psychiatry. 2012 Oct 15;72(8):620-8
references: 22883433
references: Neurosci Res. 2011 Nov;71(3):289-93
references: 21801761
references: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9397-402
references: 18599437
references: Science. 1999 Sep 24;285(5436):2129-33
references: 10497131
references: Science. 2008 Jul 11;321(5886):218-23
references: 18621663
references: Biochem Biophys Res Commun. 2003 Nov 28;311(4):1159-71
references: 14623302
references: J Neuroimmunol. 2013 Feb 15;255(1-2):70-4
references: 23110937
references: Cell. 2012 Dec 21;151(7):1581-94
references: 23260144
references: Neuron. 2008 Dec 26;60(6):1022-38
references: 19109909
references: Immunity. 1998 Jun;8(6):703-11
references: 9655484
references: Dev Neurobiol. 2012 Oct;72(10):1277-87
references: 22753382
references: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8456-60
references: 21531906
references: Dev Neurobiol. 2012 Oct;72(10):1272-6
references: 22488761
references: Dev Cell. 2007 Mar;12(3):377-89
references: 17336904
references: J Neurosci. 2007 Sep 12;27(37):10037-46
references: 17855618
references: Nat Neurosci. 2011 Apr;14(4):442-51
references: 21358642
references: J Neurosci. 1997 Jan 1;17(1):58-69
references: 8987736
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16999-7004
references: 20837535
references: J Med Genet. 2012 Feb;49(2):96-103
references: 22187495
references: Trends Mol Med. 2011 Jul;17(7):389-94
references: 21482187
references: PLoS One. 2012;7(4):e34863
references: 22496871
references: Mol Cell Neurosci. 2013 Sep;56:39-49
references: 23511190
references: Trends Immunol. 2007 Mar;28(3):115-23
references: 17261379
references: J Biol Chem. 1996 Oct 25;271(43):26659-63
references: 8900141
references: J Neurosci. 2009 May 20;29(20):6700-9
references: 19458239
references: Hum Immunol. 2004 Apr;65(4):291-302
references: 15120184
references: Brain Behav Immun. 2012 Oct;26(7):1122-7
references: 22884899
references: Brain Behav Immun. 2008 May;22(4):469-86
references: 18023140
references: Neuron. 2009 Nov 25;64(4):463-70
references: 19945389
references: J Autism Dev Disord. 2010 Dec;40(12):1423-30
references: 20414802