The Cerebellum

, Volume 16, Issue 1, pp 40–54 | Cite as

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

  • James Cairns
  • Doug Swanson
  • Joanna Yeung
  • Anna Sinova
  • Ronny Chan
  • Praneetha Potluri
  • Price Dickson
  • Guy Mittleman
  • Dan Goldowitz
Original Paper


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.


Autism Mouse Cerebellum Pathology Neuroglia Chimeras 


Compliance with Ethical Standards

All procedures including animal care, breeding, rotarod, and histology were in accordance with UBC and Canadian Council on Animal Care (CCAC) guidelines for animal care (protocol numbers A12-0190 and A13-0177).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12311_2015_756_MOESM1_ESM.doc (106 kb)
ESM 1 (DOC 105 kb)
12311_2015_756_MOESM2_ESM.ppt (8.2 mb)
Supplementary Figure S1 Expression of the pro-inflammatory marker iNOS in Iba1 positive microglia in the cerebellar cortex of Lurcher chimeras with the fewest Purkinje cells. iNOS, Iba1 and DAPI immunofluorescence showing the expression of iNOS in cerebellar PCs in a Lurcher wildtype (+/+) mouse (top left panel) and a Group #4 chimera (bottom left panel) (with mild loss of cerebellar PCs) in comparison to iNOS expression in Iba1 positive microglia in the cerebellar cortex of a Lc/+ mutant mouse (top right panel) and an ataxic Group #2 chimera (bottom right panel) (with severe loss of cerebellar PCs). (PPT 8389 kb)
12311_2015_756_MOESM3_ESM.ppt (2.8 mb)
Supplementary Figure S2 Co-localization of the pro-inflammatory marker iNOS with Iba1 positive microglia in the cerebellar cortex of Lurcher chimeras with the fewest Purkinje cells. Photomicrograph showing Iba1 positive microglia expressing the pro-inflammatory marker iNOS. Expression of iNOS is not microglia specific and iNOS also appears to be abundantly expressed throughout the molecular layer of Lc/+ mutant mice and chimeras with the most severe cerebellar pathology. Insets show higher magnification photomicrographs of the expression of iNOS and Iba1 in amoeboid-like microglia found in the molecular layer of the cerebellar cortex. (PPT 2819 kb)
12311_2015_756_MOESM4_ESM.ppt (144 kb)
Supplementary Figure S3 Regression Analyses show inverse relationships between left cerebellum PC numbers and cFos expression in the IGL, CN neurons and the density of Iba1 positive microglia in the cerebellar cortex. The top left panel shows the relationship between left cerebellum PC numbers and the density of cFos positive cells in the IGL of 39 Lurcher chimeras. The top right panel shows the relationship between left cerebellum PC numbers and the density of cFos positive CN neurons in 13 Lurcher chimeras. The bottom panel shows the relationship between left cerebellum PC numbers and the density of Iba1 positive microglia in the cerebellar cortex of 19 Lurcher chimeras. r is the correlation coefficient for each of the regression analyses and is shown in each of the panels in the figure. (PPT 144 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • James Cairns
    • 1
    • 2
    • 3
    • 4
  • Doug Swanson
    • 1
    • 2
    • 3
  • Joanna Yeung
    • 1
    • 2
    • 3
  • Anna Sinova
    • 1
    • 2
    • 3
    • 4
  • Ronny Chan
    • 1
    • 2
    • 3
  • Praneetha Potluri
    • 1
    • 2
    • 3
  • Price Dickson
    • 6
  • Guy Mittleman
    • 5
  • Dan Goldowitz
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  2. 2.Centre for Molecular Medicine and TherapeuticsUniversity of British ColumbiaVancouverCanada
  3. 3.Child and Family Research InstituteUniversity of British ColumbiaVancouverCanada
  4. 4.Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain HealthUniversity of British ColumbiaVancouverCanada
  5. 5.Department of Psychological ScienceBall State UniversityMuncieUSA
  6. 6.The Jackson LaboratoryBar HarborUSA

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