Mutations in the() gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology ofmutation-related PD, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes ofmutation-related PD have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S. Through multiple behavioral tests, including light-dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail-suspension test, we found that anxiety/depression-like behavior appeared in middle-aged (43-52 weeks) Tg mice before the onset of PD-like motor dysfunction. These behavioral tests were performed using both male and female mice, and there were no sex-related differences in behavioral changes in the middle-aged Tg mice. Along with behavioral changes, serotonin levels also significantly declined in the hippocampus of Tg mice. Additionally, increases in the expression of the 5-HTreceptor (5-HTR) grew more significant with aging and were detected in the hippocampus, amygdala, and dorsal raphe nucleus.study using the serotonergic RN46A and hippocampal HT22 cells showed that 5-HTR upregulation was related to enhanced expression of LRRK2 G2019S and was attenuated by the LRRK2 inhibitor LRRK2-IN-1. Wild-type LRRK2 had no significant effect on 5-HTR transcription. The present study provides the firstandevidence demonstrating abnormal regulation of 5-HTR along with the manifestation of anxiety/depression-like, nonmotor symptom in PD related to LRRK2.Parkinson's disease (PD), the second most common neurodegenerative disorder, is clinically characterized by motor dysfunctions. In most cases, various nonmotor symptoms present several years before the onset of the classical motor features of PD and severely affect the quality of life of patients. Here, we demonstrate the causative role of(), a common PD-linked mutation, in the development of anxiety/depression-like behaviors. We found that age-dependent 5-HTreceptor upregulation in the hippocampus, amygdala, and dorsal raphe nucleus is accompanied by the expression of themutant phenotype. Our findings demonstrating a potential mechanism for nonmotor psychiatric symptoms produced bymutation suggest that directly targeting the 5-HTreceptor can improve the therapeutic efficacy of drugs for PD-associated depression. leucine-rich repeat kinase 2LRRK2LRRK2LRRK2In vitro in vivo in vitro leucine-rich repeat kinase 2LRRK2LRRK2LRRK2 1A1A1A1A1A1A1A SIGNIFICANCE STATEMENT
