Theranostics 2021; 11(8):3760-3780. doi:10.7150/thno.53316

Research Paper

Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery

Yuhui Lin1✉*, Mengcheng Yao1*, Haiyin Wu1*, Feng Wu1, Shiying Cao1, Huanyu Ni1, Jian Dong1, Di Yang1, Yanyu Sun3, Xiaolin Kou1, Jun Li1, Hui Xiao1, Lei Chang1, Jin Wu3, Yan Liu2, Chunxia Luo1, Dongya Zhu1,2,3✉

1. Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
2. Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 211166, China.
3. Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Lin Y, Yao M, Wu H, Wu F, Cao S, Ni H, Dong J, Yang D, Sun Y, Kou X, Li J, Xiao H, Chang L, Wu J, Liu Y, Luo C, Zhu D. Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery. Theranostics 2021; 11(8):3760-3780. doi:10.7150/thno.53316. Available from https://www.thno.org/v11p3760.htm

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Abstract

Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation.

Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery.

Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure.

Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.

Keywords: environmental enrichment, GAT-1, stroke, plasticity, functional recovery