title: Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model.
abstract: Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases.
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine , Maebashi, Japan ; Department of Physiology, Faculty of Medicine Universitas Padjadjaran , Bandung, Indonesia.
authors.forename: Fathul
authors.initials: F
authors.lastname: Huda
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine , Maebashi, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Konno
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine , Maebashi, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsuzaki
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine , Maebashi, Japan ; Department of Physiology, Faculty of Medicine Universitas Padjadjaran , Bandung, Indonesia.
authors.forename: Hanna
authors.initials: H
authors.lastname: Goenawan
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine , Maebashi, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai