Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer's disease

Zijuan Zhang; Ying Jing; Yajing Ma; Dongxiao Duan; Bo Li; Christian Hölscher; Cheng Li; Jingwen Wei; Aishe Gao; Lizhi Shang; Feng Tao; Ying Xing

doi:10.1016/j.bbrc.2020.03.004

Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer's disease

Biochem Biophys Res Commun. 2020 May 14;525(4):928-935. doi: 10.1016/j.bbrc.2020.03.004. Epub 2020 Mar 12.

Authors

Zijuan Zhang¹, Ying Jing², Yajing Ma², Dongxiao Duan², Bo Li², Christian Hölscher³, Cheng Li², Jingwen Wei², Aishe Gao⁴, Lizhi Shang³, Feng Tao⁵, Ying Xing⁶

Affiliations

¹ Department of Physiology, Basic Medical School of Zhengzhou University, Zhengzhou, 450052, China; Experimental Teaching Center, Basic Medical School of Henan University of Chinese Medicine, Zhengzhou, 450046, China.
² Department of Physiology, Basic Medical School of Zhengzhou University, Zhengzhou, 450052, China.
³ Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
⁴ Experimental Teaching Center, Basic Medical School of Henan University of Chinese Medicine, Zhengzhou, 450046, China.
⁵ Department of Physiology, Basic Medical School of Zhengzhou University, Zhengzhou, 450052, China; Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX, 75246, USA; Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX, USA.
⁶ Department of Physiology, Basic Medical School of Zhengzhou University, Zhengzhou, 450052, China. Electronic address: xingy@zzu.edu.cn.

PMID: 32173530
DOI: 10.1016/j.bbrc.2020.03.004

Abstract

The changes of local field potentials (LFP, mainly gamma rhythm and theta rhythm) in the brain are closely related to learning and memory formation. Reduced gamma rhythm (20-50 Hz) and theta rhythm (4-10 Hz) has been observed in the progression of Alzheimer's disease (AD), but it is not clear whether it is related to cognition in AD. Here, we investigated behaviorally driven gamma rhythm and theta rhythm in APP/PS1 mice, and optogenetically stimulated GABAergic neurons in the brain to better understand the relationship between the changes of LFP, cognition, and cellular pathologies. Optogenetically driving GABAergic neurons rescued memory formation in a water maze task and normalized theta and gamma rhythm in the EEG. Furthermore, the optogenetic stimulation alleviated neuroinflammation and levels of amyloid-β (Aβ)1-42 fragments, and induced autophagy. GABA blockers also reversed the normalization of theta and gamma rhythms in the brain by optogenetic stimulation. The results demonstrate that stimulation of GABAergic interneurons not only rescues LFP rhythms and memory formation, but furthermore activates autophagy and reduces neuroinflammation, which have beneficial additional effects such as clearing amyloid. This is a proof of concept for a novel therapeutic approach to AD treatment.

Keywords: AD Mice; Autophagy; GABAergic neurons; LFP; Neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / pathology
Alzheimer Disease / physiopathology*
Amyloid beta-Peptides / metabolism*
Animals
Autophagy / physiology*
Disease Models, Animal
GABAergic Neurons / physiology*
Gamma Rhythm
Hippocampus / physiopathology
Learning
Male
Mice
Mice, Mutant Strains
Morris Water Maze Test
Optogenetics / methods
Spatial Memory
Theta Rhythm

Substances

Amyloid beta-Peptides