Behavioral characterization of dysbindin-1 deficient sandy mice.
Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we studied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not significantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activating effect of a low dose of d-amphetamine (2.5 mg/kg i.p.), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced locomotor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants.
Bhardwaj
Sanjeev K
SK
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 LaSalle Boul, Montreal H4H 1R3, QC, Canada.
Baharnoori
Moogeh
M
Sharif-Askari
Bahram
B
Kamath
Aarthi
A
Williams
Sylvain
S
Srivastava
Lalit K
LK
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005239:Fear / Q000502:physiology; D005838:Genotype; D006185:Habituation, Psychophysiologic / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D007274:Injections, Intraperitoneal; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D021641:Recognition, Psychology / Q000502:physiology
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D000661:Amphetamine; D003913:Dextroamphetamine