title: Abnormalities in the Structure and Function of Cerebellar Neurons and Neuroglia in the Lc/+ Chimeric Mouse Model of Variable Developmental Purkinje Cell Loss.
abstract: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired and disordered language, decreased social interactions, stereotyped and repetitive behaviors, and impaired fine and gross motor skills. It has been well established that cerebellar abnormalities are one of the most common structural changes seen in the brains of people diagnosed with autism. Common cerebellar pathology observed in autistic individuals includes variable loss of cerebellar Purkinje cells (PCs) and increased numbers of reactive neuroglia in the cerebellum and cortical brain regions. The Lc/+ mutant mouse loses 100 % of cerebellar PCs during the first few weeks of life and provided a valuable model to study the effects of developmental PC loss on underlying structural and functional changes in cerebellar neural circuits. Lurcher (Lc) chimeric mice were also generated to explore the link between variable cerebellar pathology and subsequent changes in the structure and function of cerebellar neurons and neuroglia. Chimeras with the most severe cerebellar pathology (as quantified by cerebellar PC counts) had the largest changes in cFos expression (an indirect reporter of neural activity) in cerebellar granule cells (GCs) and cerebellar nucleus (CN) neurons. In addition, Lc chimeras with the fewest PCs also had numerous reactive microglia and Bergmann glia located in the cerebellar cortex. Structural and functional abnormalities observed in the cerebella of Lc chimeras appeared to be along a continuum, with the degree of pathology related to the number of PCs in individual chimeras.
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: James
authors.initials: J
authors.lastname: Cairns
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
authors.forename: Doug
authors.initials: D
authors.lastname: Swanson
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
authors.forename: Joanna
authors.initials: J
authors.lastname: Yeung
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: Anna
authors.initials: A
authors.lastname: Sinova
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
authors.forename: Ronny
authors.initials: R
authors.lastname: Chan
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
authors.forename: Praneetha
authors.initials: P
authors.lastname: Potluri
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Price
authors.initials: P
authors.lastname: Dickson
authors.affiliation: Department of Psychological Science, Ball State University, Muncie, IN, 47306, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Mittleman
authors.affiliation: Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.|Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.|Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.|Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3. dang@cmmt.ubc.ca.
authors.forename: Dan
authors.initials: D
authors.lastname: Goldowitz
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder; D016923:Cell Death; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D002678:Chimera; D005260:Female; D015870:Gene Expression; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000502:physiology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D045442:Rotarod Performance Test; D012720:Severity of Illness Index
chemical_list: D016760:Proto-Oncogene Proteins c-fos
keywords: Autism; Cerebellum; Chimeras; Mouse; Neuroglia; Pathology
references.citation: Nature. 1997 Aug 21;388(6644):769-73
references.pmid: 9285588
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1377-84
references.pmid: 15950011
references.citation: J Autism Dev Disord. 2008 Apr;38(4):644-56
references.pmid: 17805956
references.citation: Eur J Neurosci. 2003 Oct;18(7):2002-10
references.pmid: 14622233
references.citation: Cogn Psychol. 2000 Aug;41(1):49-100
references.pmid: 10945922
references.citation: Neuron. 1992 Jan;8(1):13-23
references.pmid: 1730004
references.citation: Neurosci Lett. 2006 Mar 27;396(2):91-6
references.pmid: 16356646
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):23-36
references.pmid: 19096368
references.citation: Cerebellum. 2012 Sep;11(3):777-807
references.pmid: 22370873
references.citation: Proc Natl Acad Sci U S A. 1976 Jan;73(1):208-12
references.pmid: 1061118
references.citation: Neuron. 2014 Mar 19;81(6):1282-1289
references.pmid: 24656250
references.citation: Neurobiol Learn Mem. 2010 Sep;94(2):220-8
references.pmid: 20566377
references.citation: Anat Sci Int. 2002 Jun;77(2):94-108
references.pmid: 12418089
references.citation: J Neuroinflammation. 2013 May 15;10:65
references.pmid: 23672668
references.citation: Anat Embryol (Berl). 1985;171(2):245-52
references.pmid: 3985373
references.citation: J Neurosci. 1982 Oct;2(10):1494-8
references.pmid: 7119869
references.citation: J Comp Neurol. 2002 Oct 28;452(4):311-23
references.pmid: 12355415
references.citation: J Chem Neuroanat. 2002 Mar;23(3):157-70
references.pmid: 11861123
references.citation: Int J Dev Neurosci. 2004 Apr;22(2):73-86
references.pmid: 15036382
references.citation: J Hirnforsch. 1995;36(4):509-17
references.pmid: 8568221
references.citation: J Neurosci. 2002 Jan 1;22(1):183-92
references.pmid: 11756501
references.citation: Nature. 2012 Sep 20;489(7416):385-90
references.pmid: 22914087
references.citation: Prog Neurobiol. 1991;36(6):437-63
references.pmid: 1947173
references.citation: Physiol Behav. 1993 Jul;54(1):41-4
references.pmid: 8327607
references.citation: J Neuropathol Exp Neurol. 2007 Mar;66(3):169-76
references.pmid: 17356378
references.citation: Neuron. 2008 Mar 27;57(6):819-26
references.pmid: 18367083
references.citation: J Comp Neurol. 2002 Jun 3;447(3):210-7
references.pmid: 11984816
references.citation: Annu Rev Physiol. 2001;63:847-69
references.pmid: 11181978
references.citation: Brain Res. 1983 Oct;312(1):41-7
references.pmid: 6652508
references.citation: J Neurophysiol. 2005 Aug;94(2):1236-51
references.pmid: 16061491
references.citation: J Neurol Sci. 1977 Oct;34(1):121-9
references.pmid: 915533
references.citation: J Neurophysiol. 2004 Feb;91(2):1102-7
references.pmid: 14534284
references.citation: Neuron. 1997 Sep;19(3):665-78
references.pmid: 9331356
references.citation: Brain. 1998 May;121 ( Pt 5):889-905
references.pmid: 9619192
references.citation: Cerebellum. 2009 Sep;8(3):277-90
references.pmid: 19238501
references.citation: J Child Neurol. 2003 Jul;18(7):463-70
references.pmid: 12940651
references.citation: Annu Rev Neurosci. 2011;34:89-103
references.pmid: 21438687
references.citation: J Neurosci. 1989 Oct;9(10):3454-62
references.pmid: 2795133
references.citation: Curr Biol. 1999 Apr 22;9(8):445-8
references.pmid: 10226030
references.citation: J Neurosci Methods. 1989 Sep;29(3):261-5
references.pmid: 2507830
references.citation: Int J Dev Neurosci. 2005 Apr-May;23(2-3):183-7
references.pmid: 15749244
references.citation: Philos Trans R Soc Lond B Biol Sci. 1979 Oct 11;287(1020):167-201
references.pmid: 41272
references.citation: Ann Neurol. 2005 Jan;57(1):67-81
references.pmid: 15546155
references.citation: Brain Res. 2007 Apr 6;1140:26-40
references.pmid: 16942761
references.citation: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7309-14
references.pmid: 18477700
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):492-7
references.pmid: 24344303
references.citation: Brain. 1998 Apr;121 ( Pt 4):561-79
references.pmid: 9577385
references.citation: Neuron. 1999 Jan;22(1):103-14
references.pmid: 10027293
references.citation: Cerebellum. 2011 Sep;10(3):504-14
references.pmid: 21104177
references.citation: Glia. 2014 Jun;62(6):956-63
references.pmid: 24615726
references.citation: Biol Psychiatry. 2010 Aug 15;68(4):368-76
references.pmid: 20674603
references.citation: Glia. 2013 Feb;61(2):254-72
references.pmid: 23047288
references.citation: J Neurosci. 2012 Aug 29;32(35):12093-101
references.pmid: 22933793
references.citation: Brain Res. 2007 Apr 6;1140:4-18
references.pmid: 16412991
references.citation: Exp Neurol. 1988 Nov;102(2):261-3
references.pmid: 3141205
references.citation: Cerebellum. 2008;7(3):406-16
references.pmid: 18587625
references.citation: Science. 1965 May 28;148(3674):1232-3
references.pmid: 14280005
references.citation: Anat Rec. 1946 Feb;94:239-47
references.pmid: 21015608
references.citation: Nat Neurosci. 2005 Aug;8(8):1059-68
references.pmid: 16007083
references.citation: Am J Psychiatry. 1986 Jul;143(7):862-6
references.pmid: 3717426
references.citation: N Engl J Med. 1988 May 26;318(21):1349-54
references.pmid: 3367935
references.citation: Science. 1988 Jun 3;240(4857):1328-31
references.pmid: 3131879
references.citation: Ann N Y Acad Sci. 2007 Dec;1121:355-75
references.pmid: 17698989
references.citation: Trends Neurosci. 2008 Mar;31(3):137-45
references.pmid: 18258309