Parvalbumin interneurons regulate rehabilitation-induced functional recovery after stroke and identify a rehabilitation drug

Naohiko Okabe (), Xiaofei Wei, Farah Abumeri, Jonathan Batac, Mary Hovanesyan, Weiye Dai, Srbui Azarapetian, Jesus Campagna, Nadia Pilati, Agostino Marasco, Giuseppe Alvaro, Martin J. Gunthorpe, John Varghese, Steven C. Cramer, Istvan Mody and S. Thomas Carmichael ()
Additional contact information
Naohiko Okabe: UCLA
Xiaofei Wei: UCLA
Farah Abumeri: UCLA
Jonathan Batac: UCLA
Mary Hovanesyan: UCLA
Weiye Dai: UCLA
Srbui Azarapetian: UCLA
Jesus Campagna: UCLA
Nadia Pilati: Istituto di Ricerca Pediatrica Citta’ della Speranza
Agostino Marasco: Istituto di Ricerca Pediatrica Citta’ della Speranza
Giuseppe Alvaro: Istituto di Ricerca Pediatrica Citta’ della Speranza
Martin J. Gunthorpe: Stevenage Bioscience Catalyst
John Varghese: UCLA
Steven C. Cramer: California Rehabilitation Institute
Istvan Mody: UCLA
S. Thomas Carmichael: UCLA

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Motor disability is a critical impairment in stroke patients. Rehabilitation has a limited effect on recovery; but there is no medical therapy for post-stroke recovery. The biological mechanisms of rehabilitation in the brain remain unknown. Here, using a photothrombotic stroke model in male mice, we demonstrate that rehabilitation after stroke selectively enhances synapse formation in presynaptic parvalbumin interneurons and postsynaptic neurons in the rostral forelimb motor area with axonal projections to the caudal forelimb motor area where stroke was induced (stroke-projecting neuron). Rehabilitation improves motor performance and neuronal functional connectivity, while inhibition of stroke-projecting neurons diminishes motor recovery. Stroke-projecting neurons show decreased dendritic spine density, reduced external synaptic inputs, and a lower proportion of parvalbumin synapse in the total GABAergic input. Parvalbumin interneurons regulate neuronal functional connectivity, and their activation during training is necessary for recovery. Furthermore, gamma oscillation, a parvalbumin-regulated rhythm, is increased with rehabilitation-induced recovery in animals after stroke and stroke patients. Pharmacological enhancement of parvalbumin interneuron function improves motor recovery after stroke, reproducing rehabilitation recovery. These findings identify brain circuits that mediate rehabilitation-recovery and the possibility for rational selection of pharmacological agents to deliver the first molecular-rehabilitation therapeutic.

Date: 2025
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DOI: 10.1038/s41467-025-57860-0

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