Regulation of neural development in the striatum by Zswim6 gene

• Main Authors: Wan-Ting Lin, 林婉婷
• Other Authors: Fu-Chin Liu
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/h3bb6s

碩士 === 國立陽明大學 === 神經科學研究所 === 106 === Zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is expressed in early stages of mouse embryos. Zswim6 is expressed in the LGE (striatal primordium) and MGE (which generates cortical GABAergic interneurons) of E13.5 mouse brain. The neurobiological function of Zswim6 in the developing mouse brain is yet unclear. On the other hand, clinical study has reported that Zswim6 mutation is associated with schizophrenia. My thesis was to study the neurobiological function of Zswim6 in the developing mouse brain by analyzing Zswim6 null mutant mice and Zswim6 striatum-specific conditional knockout mice. In the first part of thesis, we injected BrdU to label proliferating cells in the pregnant mice at E13.5. Then we double-immunostained BrdU and proliferative marker Ki67 for S-phase analysis. Immunostaing data showed no significant change in BrdU and Ki67-double positive cells in E13.5 LGE and MGE between wild type and Zswim6 null mutant mice, suggesting that Zswim6 is not required to maintain proliferation of neural progenitor cells in LGE and MGE. Next, we screened the genes that might be regulated by Zswim6 in E15.5 striatum by RNA sequencing. RNA sequencing data indicated that some spine formation genes were changed in Zswim6 null mutant striatum One of the gene was ErbB4 that was expressed in GABAergic interneurons derived from the MGE. In the second part of thesis, we analyzed ErbB4 expression pattern in Zswim6 null knockout mice. Decreased expression of ErbB4 was observed in E13.5, E15.5 and postnatal day 0 (P0) in the cortex and striatum of Zswim6 null knockout mice. We also found that both parvalbumin (PV)- and ErbB4-positive interneurons were decreased in M1, S1 cortex and the straitum at P60. Somatostatin (SOM)-, calretinin (CR)- and nNOS-positive interenurons were not changed in the cortex and striatum of Zswim6 null knockout mice compared to wild type mice. In the third part of thesis, Zswim6 was expressed in the LGE and MGE. Striatum is derived from the LGE, and the striatum regulate motor function. Some populations of cortical GABAergic interneurons were derived from the MGE, and they regulate cortical neural activity. We then analyzed the function of Zswim6 using a series of behavioral tests: open-field test, rotarod, prepulse inhibition, social interaction, marble-burying, food reward conditioning test and elevated zero maze. Open-field test showed that general locomotion was changed in the Zswim6 null knockout mice. Rotarod test showed that there were deficits in motor learning and motor coordination in Zswim6 null knockout mice. Pre-pulse inhibition test showed no change in startle and pre-pulse responses in Zswim6 null knockout mice. Social interaction test showed that there were deficits in social interaction in Zswim6 null knockout mice. Marble burying and the elevated zero maze show that there was a significant increase of anxiety in Zswim6 knockout mice. Taken together, Zswim6 null knockout mice had deficits in motor learning, motor coordination, social interaction, and they had high levels of anxiety compared to wild type mice. In the fourth part of thesis, we studied the role of Zswim6 in the striatum using the striatum-specific Rgs9-Cre; Zswim6f/f conditional knockout mice. Decreased density of dendritic spines was observed in striatal neurons of Rgs9-Cre; Zswim6f/f conditional knockout mice at P14 compared to the control Rgs9-Cre; Zswim6f/+ conditional knockout mice. Open-field test showed no changes in general locomotion in Rgs9-Cre; Zswim6f/f conditional knockout mice. Rotarod test showed that Rgs9-Cre; Zswim6f/f conditional knockout mice performed normally in accelerating speed task of rotarod assay, but they had a deficit at the highest speed 44 rpm of constant speed task of rotarod assay. Taken together, Rgs9-Cre; Zswim6f/f conditional knockout mice showed decreases in dendritic spines and they had some deficits in motor coordination. In summary, our study suggests that Zswim6 is not required to maintain proliferation of neural progenitor cells in the LGE and MGE. Zswim6 null knockout mice had deficits in motor learning; motor coordination, social interaction and they were more anxious compared to wild type mice. Rgs9-Cre; Zswim6f/f conditional knockout mice showed decreases of dendritic spines of striatal neurons and some deficits in motor coordination. The mechanisms by which Zswim6 regulates spine formation, ErbB4-positive subpopulation of cortical interneurons and behavioral functions awaits future studies