ERRγ Ligand Regulates Adult Neurogenesis and Depression-like Behavior in a LRRK2-G2019S-associated Young Female Mouse Model of Parkinson’s Disease

• Published in: Neurotherapeutics 2022-07, Vol.19 (4), p.1298-1312
• Main Authors: Kim, Hyo In, Lim, Juhee, Choi, Hyo-Jung, Kim, Seok-Ho, Choi, Hyun Jin
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Cell differentiation; Dendritic spines; Dentate gyrus; Depression - genetics; Disease Models, Animal; Dopamine receptors; Doublecortin Domain Proteins; Doublecortin protein; Estrogens; Female; Hippocampus; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Ligands; LRRK2 protein; Male; Mental depression; Mice; Mice, Transgenic; Movement disorders; Mutation; Neurobiology; Neurodegenerative diseases; Neurogenesis; Neurology; Neurosciences; Neurosurgery; Original; Original Article; Orphan Nuclear Receptors; Parkinson Disease - metabolism; Parkinson's disease; Protein Serine-Threonine Kinases; Therapeutic targets; TrkB receptors; Tropomyosin
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-022-01244-5

Adult neurogenesis, a process controlling the proliferation to maturation of newly generated neurons in the post-developmental brain, is associated with various brain functions and pathogenesis of neuropsychological diseases, such as Parkinson's disease (PD) and depression. Because orphan nuclear receptor estrogen-related receptor γ (ERRγ) plays a role in the differentiation of neuronal cells, we investigated whether an ERRγ ligand enhances adult neurogenesis and regulates depressive behavior in a LRRK2-G2019S-associated mouse model of PD. Young female LRRK2-G2019S mice (7–9 weeks old) showed depression-like behavior without dopaminergic neuronal loss in the nigrostriatal pathway nor motor dysfunction. A significant decrease in adult hippocampal neurogenesis was detected in young female LRRK2-G2019S mice, but not in comparable male mice. A synthetic ERRγ ligand, ( E )-4-hydroxy- N '-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2), ameliorated depression-like behavior in young female LRRK2-G2019S mice and enhanced neurogenesis in the hippocampus, as evidenced by increases in the number of bromodeoxyuridine/neuronal nuclei-positive cells and in the intensity and number of doublecortin-positive cells in the hippocampal dentate gyrus (DG). Moreover, HPB2 significantly increased the number of spines and the number and length of dendrites in the DG of young female LRRK2-G2019S mice. Furthermore, HPB2 upregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, one of the important factors regulating neurogenesis, as well as phosphorylated cAMP-response element binding protein-positive cells in the DG of young female LRRK2-G2019S mice. Together, these results suggest ERRγ as a novel therapeutic target for PD-associated depression by modulating adult neurogenesis and BDNF/TrkB signaling.