Division of Neurosurgery, Department of Clinical Sciences, Laboratory for Experimental Brain Research, Lund University, Lund 221 84, Sweden.
Department of Radiology, Washington University, Saint Louis, MO 63110, USA.
Brain. 2024 Jan 4;147(1):186-200. doi: 10.1093/brain/awad293.
Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.
中风导致局部神经连接中断和全脑神经元网络功能障碍，导致神经功能缺损。除了缺血性中风的超急性期之外，没有临床批准的药物治疗可以缓解感觉运动障碍。中风后功能恢复涉及新的或替代的神经元回路的形成，包括现有的神经连接。5 型代谢型谷氨酸受体（mGluR5）已被证明可以调节大脑的可塑性和功能，并且是中风以外的神经疾病的治疗靶点。我们研究了 mGluR5 是否会影响局灶性缺血的啮齿动物模型的功能恢复和网络重组。通过多种行为测试，我们观察到，在中风后 2 天或 10 天开始用 mGluR5 的负变构调节剂（MTEP、fenobam 和 AFQ056）治疗 12 天，恢复了丧失的感觉运动功能，而不会减小梗塞面积。治疗开始后数小时内即可出现恢复，并且在随后的 12 天内逐渐进展。用正变构调节剂 VU0360172 激活 mGluR5 可防止恢复，并且 mGluR5 敲除小鼠与野生型小鼠相比，恢复速度加快。中风后，丰富环境的多感官刺激增强了恢复，而 VU0360172 则阻止了这种恢复，这表明 mGluR5 在丰富环境介导的恢复中起作用。此外，与单独使用 MTEP 或丰富环境相比，MTEP 治疗与丰富环境结合使用可提供额外的恢复增强作用。通过光学内源信号成像，我们观察到中风后静息状态功能连接在全脑范围内受到破坏，而 mGluR5 抑制可防止这种破坏在对侧感觉运动和双侧视觉皮层的不同区域发生。中风后，小鼠和中风患者组织样本中的 mGluR5 蛋白水平没有变化。我们的结论是，中风后感觉运动功能的神经元回路受到 mGluR5 依赖性适应不良可塑性机制的抑制，这种机制可以通过 mGluR5 抑制来恢复。中风后急性后期用 mGluR5 NAMs 联合康复训练治疗可能代表一种新的中风后急性后期治疗方法。
