title: Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder.
abstract: Patients with type II lissencephaly, a neuronal migration disorder with ectopic neurons, suffer from severe mental retardation, including learning deficits. There is no effective therapy to prevent or correct the formation of neuronal ectopia, which is presumed to cause cognitive deficits. We hypothesized that learning deficits were not solely caused by neuronal ectopia and that postnatal gene therapy could improve learning without correcting the neuronal ectopia formed during fetal development. To test this hypothesis, we evaluated spatial learning of cerebral cortex-specific proteinO-mannosyltransferase 2 (POMT2, an enzyme required forO-mannosyl glycosylation) knockout mice and compared to the knockout mice that were injected with an adeno-associated viral vector (AAV) encoding POMT2 into the postnatal brains with Barnes maze. The data showed that the knockout mice exhibited reduced glycosylation in the cerebral cortex, reduced dendritic spine density on CA1 neurons, and increased latency to the target hole in the Barnes maze, indicating learning deficits. Postnatal gene therapy restored functional glycosylation, rescued dendritic spine defects, and improved performance on the Barnes maze by the knockout mice even though neuronal ectopia was not corrected. These results indicate that postnatal gene therapy improves spatial learning despite the presence of neuronal ectopia.
authors.affiliation: Department of Neuroscience and Physiology, Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. huh@upstate.edu.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Neuroscience and Physiology, Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. liuyu@upstate.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and Physiology, Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. bampoek@upstate.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bampoe
authors.affiliation: Department of Neuroscience and Physiology, Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. heyonglinhyl@163.com.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Neuroscience and Physiology, Center for Vision Research, Department of Ophthalmology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. yum@upstate.edu.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
keywords: adeno-associated virus; gene therapy; neuronal migration disorder; type II lissencephaly