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Cerebellum. 2017 Feb;16(1):40-54. doi: 10.1007/s12311-015-0756-7.

Abnormalities in the Structure and Function of Cerebellar Neurons and Neuroglia in the Lc/+ Chimeric Mouse Model of Variable Developmental Purkinje Cell Loss.

Cairns J1,2,3,4, Swanson D1,2,3, Yeung J1,2,3, Sinova A1,2,3,4, Chan R1,2,3, Potluri P1,2,3, Dickson P5, Mittleman G6, Goldowitz D7,8,9,10.

Author information

1
Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
2
Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
3
Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
4
Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3.
5
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
6
Department of Psychological Science, Ball State University, Muncie, IN, 47306, USA.
7
Department of Medical Genetics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.
8
Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.
9
Child and Family Research Institute, University of British Columbia, 950 W. 28th Ave, Vancouver, BC, Canada, V5Z 4H4. dang@cmmt.ubc.ca.
10
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.

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.

KEYWORDS:

Autism; Cerebellum; Chimeras; Mouse; Neuroglia; Pathology

PMID:
26837618
DOI:
10.1007/s12311-015-0756-7
[Indexed for MEDLINE]

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