Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A.
Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.|The Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
M S
MS
Alexander
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
M J
MJ
Gasperini
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
P T
PT
Tsai
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
D E
DE
Gibbs
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
J M
JM
Spinazzola
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
J L
JL
Marshall
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
M J
MJ
Feyder
Rare Disease Research Unit, Pfizer, Cambridge, MA, USA.
M T
MT
Pletcher
Rare Disease Research Unit, Pfizer, Cambridge, MA, USA.
E L P
EL
Chekler
Rare Disease Research Unit, Pfizer, Cambridge, MA, USA.
C A
CA
Morris
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
M
M
Sahin
Neuroscience Research Unit, Pfizer Global Research and Development, Cambridge, MA, USA.
J F
JF
Harms
Neuroscience Research Unit, Pfizer Global Research and Development, Cambridge, MA, USA.
C J
CJ
Schmidt
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
R J
RJ
Kleiman
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.|The Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.|The Manton Center for Orphan Diseases, Boston, MA, USA.|Harvard Stem Cell Institute, Cambridge, MA, USA.
L M
LM
Kunkel
Neuroscience. 1993 May;54(1):167-87
8515841
Int J Impot Res. 1996 Jun;8(2):47-52
8858389
J Pathol. 2012 Sep;228(1):77-87
22653783
J Child Neurol. 2008 Feb;23(2):155-62
18056690
Ann Neurol. 2014 Oct;76(4):550-7
25042931
PLoS One. 2012;7(4):e33224
22511918
Ann Med. 2009;41(5):344-59
19172427
Behav Brain Res. 2010 Dec 1;213(2):189-94
20452381
Mol Autism. 2015 Oct 29;6:60
26527530
Nature. 2012 Aug 30;488(7413):647-51
22763451
J Cell Physiol. 2016 Jan;231(1):224-32
26097015
Neuropharmacology. 2011 Sep;61(4):665-76
21619887
J Autism Dev Disord. 2000 Dec;30(6):511-7
11261463
Neurology. 2014 Jun 10;82(23):2085-91
24808022
Vision Res. 1995 Aug;35(16):2383-93
7571473
Genes Brain Behav. 2016 Jul;15(6):558-67
27220066
Nature. 1990 Dec 20-27;348(6303):725-8
2259381
J Neurosci. 1996 May 1;16(9):2881-90
8622119
Curr Protoc Neurosci. 2011 Jul;Chapter 8:Unit 8.26
21732314
Dev Med Child Neurol. 2007 Feb;49(2):123-8
17254000
Sci Transl Med. 2012 Nov 28;4(162):162ra155
23197572
J Neurol Sci. 1971 Oct;14(2):209-13
5112213
J Dev Behav Pediatr. 2006 Dec;27(6):470-6
17164619
J Med Chem. 2012 Nov 8;55(21):9055-68
23025719
Cell Mol Neurobiol. 2013 May;33(4):513-20
23436181
Proc Natl Acad Sci U S A. 1989 Feb;86(4):1292-6
2919177
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5331-6
21402949
J Pharmacol Exp Ther. 2008 May;325(2):681-90
18287214
J Pediatr. 2012 Oct;161(4):705-9.e1
22560791
PLoS One. 2014 Sep 26;9(9):e108364
25260053
Ann Neurol. 1995 Sep;38(3):446-9
7668831
Neuromuscul Disord. 2000 Mar;10(3):194-9
10734267
J Clin Neurosci. 2011 Jan;18(1):90-5
21109441
Dev Med Child Neurol. 1981 Oct;23(5):577-90
7286451
Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19079-83
20956307
Curr Probl Pediatr. 1989 Mar;19(3):113-66
2541974
Neuromuscul Disord. 2002 Dec;12(10):917-25
12467746
J Child Neurol. 2008 May;23(5):477-81
18354150
Brain Res. 2004 Sep 3;1019(1-2):289-92
15306266
Cell. 1987 Dec 24;51(6):919-28
3319190
J Child Neurol. 2015 Oct;30(11):1472-82
25660133
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3125-30
22315408
Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R396-404
24944249
Balkan J Med Genet. 2013 Jun;16(1):21-30
24265581
J Pediatr. 2007 May;150(5):474-8
17452219
Pediatr Neurol. 2006 Apr;34(4):296-300
16638505
Neurobiol Aging. 2014 Sep;35(9):2072-8
24746365
J Neurosci. 2003 Jul 23;23(16):6452-9
12878685
Nature. 1986 Oct 16-22;323(6089):646-50
3773991
Neuropharmacology. 2013 Jan;64:268-82
22801296
J Pharmacol Exp Ther. 2012 May;341(2):396-409
22328573
J Neurogenet. 2011 Dec;25(4):120-6
22070409
Ophthalmology. 1994 May;101(5):856-65
8190471
Dev Med Child Neurol. 2016 Jan;58(1):77-84
26365034
Psychol Bull. 1979 Mar;86(2):250-9
382221
Neuropharmacology. 2012 Apr;62(5-6):1964-74
22245562
Neurobiol Dis. 2011 Sep;43(3):558-64
21601636
Pediatr Neurol. 2009 Nov;41(5):339-46
19818935
Front Syst Neurosci. 2013 May 10;7:15
23717269
Eur J Hum Genet. 2016 Apr;24(4):562-8
26081639
Ann Neurol. 2014 Oct;76(4):541-9
25042693
J Neurochem. 2016 Sep;138(6):785-805
27333343
Learn Disabil Res Pract. 2004 Aug;19(3):146-154
17710256
Rev Neurosci. 2014;25(2):177-94
24523305