title: Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).
abstract: Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Chitu
authors.affiliation: Institute for Brain Disorders and Neural Regeneration, Departments of Neurology, Neuroscience and Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Solen
authors.initials: S
authors.lastname: Gokhan
authors.affiliation: Behavioral Core Facility, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Branch
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Madhuvati
authors.initials: M
authors.lastname: Patil
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ranu
authors.initials: R
authors.lastname: Basu
authors.affiliation: Behavioral Core Facility, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Corrina
authors.initials: C
authors.lastname: Stoddart
authors.affiliation: Institute for Brain Disorders and Neural Regeneration, Departments of Neurology, Neuroscience and Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Mehler
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: richard.stanley@einstein.yu.edu.
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
mesh_terms: D000818:Animals; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D056784:Leukoencephalopathies / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D058953:Neural Stem Cells / Q000276:immunology / Q000473:pathology; D009457:Neuroglia / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D055696:Olfactory Perception / Q000502:physiology; D010641:Phenotype; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics; D066127:White Matter / Q000276:immunology / Q000473:pathology
chemical_list: C000604004:Csf1r protein, mouse; D016207:Cytokines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
keywords: ALSP; CSF-1R; Dysmyelination; GM-CSF; HDLS; Leukodystrophy; Microglia