| dc.description.abstract | Infantile spasm (IS) is a severe epileptic seizure that usually occurs before one year of age. The human genetic study suggested that KLHL17 is a high-risk gene of IS. In mice, Klhl17 encodes a brain-specific actin-binding protein. It also acts as a substrate receptor of CUL3 to degrade GRIK2/GLUR6 (a subunit of the kainite receptor). We have previously reported that KLHL17 regulates dendritic spine enlargement and synaptic activity. However, the in vivo function of KLHL17 remains unknown. This thesis is divided into two parts to address this question. In the first part, I use Klhl17 deletion mice to characterize the in vivo function of KLHL17. In the second part, the main goal is to assist other KLHL17-related projects in the laboratory. In the first part, although Klhl17 deletion does not affect overall brain anatomy in both male and female mice, we found that the morphology of dendritic spines exhibits sex- and region-biased differences in the hippocampal CA1 region and somatosensory cortex of Klhl17 deletion mice. I further analyzed the behavioral deficits of Klhl17 deficient mice. Consistent with the association of KLHL17 and IS, I found higher seizure susceptibility in male but not female Klhl17 deficient mice. Klhl17+/- mice also showed slightly social communication deficits in early life. Both male and female Klhl17+/- mice all exhibited social deficits, though in a specific test, female Klhl17+/- mice social deficits were not evident. However, male and female Klhl17+/- mice did not have the trait of cognitive inflexibility, and precisely, male Klhl17+/- mice showed improved results. Moreover, I found that early ultrasonic vocalization experience would alter locomotivity, spatial memory, and social behavior in male and female Klhl17+/- mice. Further, I analyzed proteomics results in the total hippocampal lysate and synaptosomal fractions to understand the possible molecular mechanism. I found some misregulated proteins affected by KLHL17 sex-differentially. However, it is still unclear whether dysregulation of those synaptic proteins is linked to dendritic spine deficits or abnormal behaviors. In the second part, majorly, I showed that KLHL17 regulates the distribution of ER in the dendritic spine upon neuronal activation. To sum up, I use different aspects and approaches to study the function of KLHL17, and much more understand the relationship between KLHL17 and neurologic disorders. | en_US |