Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease.
To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD.
Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Mei
M
Dai
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Benjamin
B
Liou
Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.|Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
Brittany
B
Swope
Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Xiaohong
X
Wang
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Wujuan
W
Zhang
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Venette
V
Inskeep
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Gregory A
GA
Grabowski
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.|Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
Ying
Y
Sun
Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.|Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States of America.
Dao
D
Pan
D000161:Acoustic Stimulation; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D005684:Gait / Q000502:physiology; D005776:Gaucher Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics*; D005963:Glucosylceramides / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D011609:Psychosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D012737:Sex Factors; D065852:Spatial Memory / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis
D005963:Glucosylceramides; D051844:alpha-Synuclein; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D005962:Glucosylceramidase