Phenotypic characterization of mice lacking exons 4-13 ofDisc1 gene in forebrain excitatory neurons

• Main Authors: Pei-Fen Siow, 蕭佩芬
• Other Authors: Li-Jen Lee
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/8f56sq

碩士 === 國立臺灣大學 === 解剖學暨細胞生物學研究所 === 107 === Schizophrenia is a chronic psychotic disorder characterized by abnormal behavior and unable to interpret the reality. One susceptibility gene related to the pathogenesis of this disorder is Disrupted-in-Schizophrenia 1 (DISC1). Overexpressed extra-short DISC1 isoform was found in a neurocognitive subgroup of schizophrenia patients from Taiwan and might be related to their deficits in sustained attention. In the present study, in order to investigate the effects of extra-short DISC1 isoform on brain structure and function, we generated forebrain-specific Disc1 knockout (FbDisc1 KO) mice in which exons 4 to 13 of Disc1 gene was removed in forebrain excitatory neurons using the Cre/loxP system. The phenotypes of male adult (8-12 weeks old) homozygote (Homo, Disc1Δ4-13/Δ4-13; Emx1-Cre) and heterozygote (Het, Disc1Δ4-13/+; Emx1-Cre) FbDisc1 KO mice were compared with age- and sex-matched controls (Emx1-Cre). Homo and Het FbDisc1 KO mice were apparently normal with no significant physical impairment and behaved normally in the open field, elevated plus maze, Y-maze, novel object recognition and pre-pulse inhibition tests. However, Homo FbDisc1 KO mice exhibited altered stress-coping response in the forced swimming test. The medial prefrontal cortex (mPFC) in rodents is involved in the stress-coping behavior, we then examined the histological features of mPFC neurons. The dendritic complexity of layer II/III pyramidal mPFC was not altered in mutants while the dendritic spines were reduced in both Homo and Het FbDisc1 KO mice. The densities of parvalbumin-positive mPFC neurons were similar among control, Het and Homo mice; however, the densities of calbindin-positive mPFC neurons were reduced in both Homo and Het FbDisc1 KO mice. Together with the prefrontal cortex, intact cortical-striatal neural network is required for sustained attention. Based on the findings in the mPFC of Homo FbDisc1 KO mice, we suggest that our Homo FbDisc1 KO mice might model the neurocognitive phenotype of schizophrenia patients with extra-short DISC1 isoform.