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Surgical Approach for Middle Cerebral Artery Occlusion and Reperfusion Induced Stroke in Mice
Published on: October 20, 2016
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Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity
Jakob Hakon1, Miriana J Quattromani1, Carin Sjölund1
1Division of Neurosurgery, Department of Clinical Sciences, Laboratory for Experimental Brain Research, Lund University, Lund 221 84, Sweden.
Brain : a Journal of Neurology
|September 1, 2023
Summary
Inhibiting the type-5 metabotropic glutamate receptor (mGluR5) with drugs restored sensorimotor function after stroke in rodents. This approach may offer new therapies for stroke recovery by targeting maladaptive plasticity.
Area of Science:
- Neuroscience
- Pharmacology
- Stroke Research
Background:
- Stroke causes neural disconnection and network dysfunction, leading to sensorimotor deficits.
- Currently, no approved drugs effectively treat sensorimotor impairments post-stroke.
- Type-5 metabotropic glutamate receptor (mGluR5) modulates brain plasticity and is a therapeutic target for neurological disorders.
Purpose of the Study:
- To investigate the role of mGluR5 in functional recovery and neural network reorganization after focal ischemia in rodents.
- To determine if mGluR5 inhibition can restore sensorimotor functions and improve network connectivity post-stroke.
Main Methods:
- Rodent models of focal ischemia were used.
- Behavioral tests assessed sensorimotor function recovery.
- Negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam, AFQ056) were administered post-stroke.
- Optical intrinsic signal imaging evaluated resting-state functional connectivity.
- Enriched environments and mGluR5 activation (VU0360172) were used to study recovery mechanisms.
Main Results:
- Treatment with mGluR5 NAMs significantly restored sensorimotor functions within hours, progressing over 12 days, without affecting infarct size.
- Recovery was blocked by mGluR5 activation and accelerated in mGluR5 knock-out mice.
- Multisensory stimulation in enriched environments enhanced recovery, an effect blocked by mGluR5 activation.
- Combined treatment with mGluR5 NAMs and enriched environments showed additive recovery benefits.
- mGluR5 inhibition prevented stroke-induced disruptions in brain-wide functional connectivity.
- mGluR5 protein levels remained unchanged post-stroke in mice and human samples.
Conclusions:
- Stroke induces mGluR5-dependent maladaptive plasticity that impairs sensorimotor function recovery.
- Inhibition of mGluR5 restores neuronal circuitry and promotes functional recovery after stroke.
- mGluR5 NAMs combined with rehabilitation may offer a novel therapeutic strategy for post-acute stroke recovery.
