1. Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery
- Author
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Hui Xiao, Chun-Xia Luo, Hai-Yin Wu, Yu-Hui Lin, Yanyu Sun, Meng-Cheng Yao, Huan-Yu Ni, Jian Dong, Yan Liu, Xiao-Lin Kou, Di Yang, Shi-Ying Cao, Feng Wu, Jun Li, Dong-Ya Zhu, Jin Wu, and Lei Chang
- Subjects
Male ,GAT-1 ,GABA Plasma Membrane Transport Proteins ,functional recovery ,medicine.medical_treatment ,Medicine (miscellaneous) ,Optogenetics ,In Vitro Techniques ,Mice ,Neuroplasticity ,Medicine ,GABA transporter ,Tonic (music) ,Animals ,Humans ,Molecular Targeted Therapy ,Precision Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Stroke ,gamma-Aminobutyric Acid ,Mice, Knockout ,Neurons ,Environmental enrichment ,Neuronal Plasticity ,biology ,business.industry ,Recovery of Function ,medicine.disease ,stroke ,Mice, Inbred C57BL ,Disease Models, Animal ,plasticity ,Corticospinal tract ,biology.protein ,environmental enrichment ,Female ,business ,Stroke recovery ,Neuroscience ,Signal Transduction ,Research Paper - 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.
- Published
- 2021