Nat Neurosci. 2021 Aug;24(8):1089-1099. doi: 10.1038/s41593-021-00864-y. | PubMed

Roy Maimon^1,2, Carlos Chillon-Marinas^1,2, Cedric E Snethlage³, Sarthak M Singhal⁴, Melissa McAlonis-Downes^1,2, Karen Ling⁵, Frank Rigo⁵, C Frank Bennett⁵, Sandrine Da Cruz^1,6, Thomas S Hnasko^4,7, Alysson R Muotri^2,3, Don W Cleveland^8,9

1. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
2. Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
3. Department of Pediatrics, Rady Children's Hospital San Diego, Stem Cell Program, Center for Academic Research and Training in Anthropogeny (CARTA), Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA.
4. Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA.
5. Ionis Pharmaceuticals, Carlsbad, CA, USA.
6. VIB-KU Leuven Center for Brain & Disease Research and Department of Neurosciences, KU Leuven, Leuven, Belgium.
7. Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
8. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA. dcleveland@health.ucsd.edu.
9. Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA. dcleveland@health.ucsd.edu.

Abstract

Methods to enhance adult neurogenesis by reprogramming glial cells into neurons enable production of new neurons in the adult nervous system. Development of therapeutically viable approaches to induce new neurons is now required to bring this concept to clinical application. Here, we successfully generate new neurons in the cortex and dentate gyrus of the aged adult mouse brain by transiently suppressing polypyrimidine tract binding protein 1 using an antisense oligonucleotide delivered by a single injection into cerebral spinal fluid. Radial glial-like cells and other GFAP-expressing cells convert into new neurons that, over a 2-month period, acquire mature neuronal character in a process mimicking normal neuronal maturation. The new neurons functionally integrate into endogenous circuits and modify mouse behavior. Thus, generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach, thereby opening prospects for production of neurons to replace those lost to neurodegenerative disease.

Presented By Roy Maimon and Carlos Chillon Marinas