ABSTRACT
Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1Δ2-3/Δ2-3 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1Δ2-3/Δ2-3 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1Δ2-3/Δ2-3 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1Δ2-3/Δ2-3 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1Δ2-3/Δ2-3 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1Δ2-3/Δ2-3 mice are associated with hyperactivity of the DMS.
Subject(s)
Compulsive Behavior/physiopathology , Nerve Tissue Proteins/metabolism , Stereotypic Movement Disorder/physiopathology , Animals , Behavior, Animal/physiology , Clozapine , Cognition , Cognitive Dysfunction/genetics , Disease Models, Animal , Exons , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/genetics , Photic StimulationABSTRACT
Seven proteinases were isolated from the fruit of snake-gourd, Trichosanthes cucumeroides Maxim. Their isozymes are all serine proteinases, and homologous in their respective molecular weights, amino acid compositions, and enzymatic properties. Their molecular weight was estimated to be about 50,000. Using casein as a substrate, the maximum activity was found in the alkaline pH region. The optimum temperature using casein was 70 degrees C at pH 7.3. The enzymes were strongly inhibited by diisopropyl fluorophosphate and not inhibited by inhibitors of sulfhydryl or metalloproteases. The reduced and S-carboxymethylated insulin B-chain was used as a substrate in an investigation of the specificity. The enzyme was found to have a wide specificity for this substrate but preferentially hydrolyzed the peptide bonds involving the carboxyl groups of charged amino acid such as S-cm-cysteine, glutamic acid, histidine, arginine, and lysine. Experimental evidence indicated that the snake-gourd proteinases are similar in their properties to cucumisin, which is isolated from the sarcocarp of melon fruit.
