Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency. Issue 7 (26th November 2019)

• Record Type: Journal Article
• Authors: Baskaran, Rathinasamy; Lai, Chuan‐Ching; Li, Wai‐Yu; Tuan, Li‐Heng; Wang, Chia‐Chuan; Lee, Lukas J.‐H.; Liu, Chih‐Min; Hwu, Hai‐Gwo; Lee, Li‐Jen
• Is Part Of: Journal of comparative neurology. Volume 528:Issue 7(2020)
• Page Start: 1157
• Page End: 1172
• Publication Date: 2019-11-26
• Subjects: amphetamine -- animal model -- dendritic spine -- dopamine receptor -- microglia -- neuronal morphology -- PRID: AB_1240433 -- PRID: AB_2094832 -- PRID: AB_477329 -- PRID: AB_668816 -- schizophrenia; Comparative neurobiology -- Periodicals; Neurology -- Periodicals; 616
• DOI: 10.1002/cne.24813
• Languages: English
• ISSNs: 0021-9967

Abstract

Abstract: Disrupted‐in‐Schizophrenia 1 ( DISC1 ) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, we generated Disc1 mutant mice by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into the C57BL/6J strain. In this study, we used heterozygous Disc1 mutant (Het) mice to evaluate the DISC1 haploinsufficiency model of schizophrenia. No changes in locomotor behaviors were observed in Het mice; however, after amphetamine injection, greater locomotor activity was observed in Het mice compared with wild‐type (WT) mice. Moreover, amphetamine‐induced elevations of c‐Fos expression and dopamine level in the striatum were greater in Het mice than in WT controls, suggesting an altered dopaminergic regulation in the striatum of Het mice. Compared with those in WTs, the striatal protein levels of dopamine transporter and D2 dopamine receptor were increased in Het mice, while D1 dopamine receptor level was decreased. DISC1 interacting proteins, GSK3α and GSK3β, were downregulated in Het mice, whereas the levels of PDE4B and CREB were not altered. Morphologically, the complexities of striatal median spiny neurons (MSNs), parvalbumin‐positive interneurons and Iba1‐positive microglia were all decreased in Het mice. The density and head diameter of dendritic spines in the MSNs of Het mice were also reduced. Our results indicate that mice lacking one WT Disc1 allele are more sensitive to psychostimulant amphetamine challenge, which might be attributed to the altered structure and function of the striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice, which could be a promising model of DISC1 haploinsufficiency. Abstract : In the striatum of Het Disc1 mutant mice, the protein levels of DAT and D2R are increased while D1R and GSK3 α/β are decreased, the complexities of MSNs, PVNs and microglia as well as the densities of MSN spine and PVN are reduced.