Motor recovery through perineuronal net modulation in a Parkinson’s disease mouse model

Abstract Perineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity. While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked. We found that transient reduction of primary motor cortex perineuronal nets by ChABC treatment in otherwise healthy adult mice resulted in temporary deficits in motor function. In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks. We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation. This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers. These findings reveal distinct roles of perineuronal net plasticity – first in response to the initial midbrain lesion and then during rescue after ChABC treatment – suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function. This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.