Motor cortex perineuronal net modulation improves motor function in a Parkinson’s disease mouse model

The 6-OHDA mouse model recapitulates midbrain dopaminergic cell loss and associated motor deficits akin to those observed in Parkinson’s disease. Emerging evidence suggests that modulating interneurons in the primary motor cortex could offer a means to mitigate symptoms. In the cortex, perineuronal nets (PNNs), a specialized extracellular matrix structure generally present around fast-spiking parvalbumin interneurons, can modulate neural activity and circuit plasticity. We found that removing PNNs through unilateral or bilateral ChABC injection in the motor cortex temporarily altered motor behavior. Surprisingly, bilateral reduced motor cortex PNNs are observed two weeks after unilateral 6-OHDA midbrain lesions, whereas five weeks after lesion, PNNs return to control levels. Subsequent bilateral ChABC injections significantly improved motor function in 6-OHDA animals only when associated with motor stimulation involving enriched housing and daily motor training. Thus, PNN modulation in the motor cortex of a Parkinson’s disease model enables local circuits to adapt to the loss of dopaminergic inputs, resulting in improved motor behavior.