Article type: Research Article
Authors: Zhang, Hongyu | Petit, Géraldine H. | Gaughwin, Philip M. | Hansen, Christian | Ranganathan, Srikanth | Zuo, Xiaoyi | Smith, Ruben | Roybon, Laurent | Brundin, Patrik | Mobley, William C. | Li, Jia-Yi;
Affiliations: Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden | Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA | Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
Note: [] Present address: Univ. Bordeaux, Institut Interdisciplinaire de Neurosciences, UMR 5297, F-33000 Bordeaux, France; CNRS, Institut Interdisciplinaire de Neurosciences, UMR 5297, F-33000 Bordeaux, France.
Note: [] Present address: Department of Neurology, West China Hospital, Sichuan University, Chengdu, 160000 Sichuan, China.
Note: [] Present address: Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. N.E., Grand Rapids, MI 49503-2518, USA.
Note: [] Correspondence to: Dr. Jia-Yi Li, Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 221 84 Lund, Sweden. Tel.: +46 46 222 0525; Fax: +46 46 222 0531; E-mail: jia-yi.li@med.lu.se
Abstract: Background: Recent studies in Huntington's disease (HD) mouse models and patients suggest that hippocampal neurons and their cholinergic afferents are involved in the cognitive deficits seen in the disease. Nerve growth factor (NGF) is an essential regulator of cholinergic neuronal survival and neurotransmission. Objective: We asked whether NGF might be involved in HD and if intra-cerebroventricular infusion of NGF can rescue hippocampal cholinergic neuronal markers, restore neurogenesis, and improve the spatial working memory in R6/1 mouse model of HD. Methods: We quantified NGF protein level by enzyme-linked immunosorbent assay (ELISA), intracerebroventricularly infused NGF, assessed cholinergic neuronal markers by Western blotting and quantitative RT-PCR, evaluated neurogenesis by immunohistochemistry, and studied spatial working memory using radial maze. Results: By quantifying NGF protein in the hippocampus of the R6/1 mice at different ages, we found progressive decreases in NGF protein levels. We then increased NGF levels in the R6/1 mice through intra-cerebroventricular infusion. We observed elevations of the cholinergic neurochemical markers vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) in the hippocampus and in the septal region, which contain the cell bodies of basal forebrain cholinergic neurons (BFCNs), but not in the striatum that harbors cholinergic interneurons. Finally, we found that NGF infusion also restored hippocampal neurogenesis and improved spatial working memory. Conclusions: Our results suggest that intracerebral injections of NGF might be a valuable therapy against cognitive symptoms in HD and should be further studied in HD animal models and patients.
Keywords: Nerve growth factor, cholinergic function, neurogenesis, huntington's disease, R6/1 mice
DOI: 10.3233/JHD-120026
Journal: Journal of Huntington's Disease, vol. 2, no. 1, pp. 69-82, 2013
