title: Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation.
abstract: Mouse models of neuronal ceroid lipofuscinosis (NCL) exhibit many features of the human disorder, with widespread regional atrophy and significant loss of GABAergic interneurons in the hippocampus and neocortex. Reactive gliosis is a characteristic of all forms of NCL, but it is unclear whether glial activation precedes or is triggered by neuronal loss. To explore this issue we undertook detailed morphological characterization of the Cln3 null mutant (Cln3(-/-)) mouse model of juvenile NCL (JNCL) that revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread loss of hippocampal interneurons that was first evident at 14 months of age. Quantitative image analysis demonstrated upregulation of markers of astrocytic and microglial activation in presymptomatic Cln3(-/-) mice at 5 months of age, many months before significant neuronal loss occurs. These data provide evidence for subtle glial responses early in JNCL pathogenesis.
authors.affiliation: Pediatric Storage Disorders Laboratory, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, King's College London, London, SE5 8AF, UK.
authors.forename: Charlie C
authors.initials: CC
authors.lastname: Pontikis
authors.forename: Claire V
authors.initials: CV
authors.lastname: Cella
authors.forename: Nisha
authors.initials: N
authors.lastname: Parihar
authors.forename: Ming J
authors.initials: MJ
authors.lastname: Lim
authors.forename: Shubhodeep
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Payam
authors.initials: P
authors.lastname: Rezaie
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
mesh_terms: D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes; D001921:Brain / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D064026:Calbindins; D002452:Cell Count / Q000379:methods; D048429:Cell Size; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000503:physiopathology*; D007150:Immunohistochemistry / Q000379:methods; D007395:Interneurons / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000502:physiology*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology / Q000503:physiopathology*; D010320:Parvalbumins / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D018709:Statistics, Nonparametric; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D064026:Calbindins; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D013004:Somatostatin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C102229:CLN3 protein, mouse; C036763:monocyte-macrophage differentiation antigen