MiR‑204‑5p modulates glial morphology and apomorphine‑induced rotational asymmetry without dopaminergic neuroprotection in a preclinical mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive nigrostriatal dopaminergic degeneration and a dysregulated neuroinflammatory environment. Here, we investigated whether intranigral delivery of a microRNA‑204‑5p mimic (miR‑204-5p) at the time of lesion modulates dopaminergic‑dependent rotational asymmetry, glial morphology, and striatal medium spiny neurons (MSNs) recruitment in a unilateral 6‑OHDA mouse model. Adult C57BL/6 mice received a unilateral striatal 6‑OHDA injection and simultaneous intranigral infusion of a synthetic miR‑204‑5p mimic or vehicle, and apomorphine‑induced rotations, rotarod performance, TH immunohistochemistry, high‑content morphometric analyses of GFAP‑positive astrocytes and IBA1‑positive microglia, and c‑Fos/DARPP‑32 expression were assessed four weeks later. In 6‑OHDA‑lesioned mice, miR‑204-5p treatment significantly reduced apomorphine‑induced contralateral rotations relative to 6‑OHDA alone, while TH‑positive neuron counts in the substantia nigra and TH‑positive fiber density in the striatum remained comparably reduced across all lesioned groups. Intranigral miR‑204-5p delivery in 6‑OHDA‑lesioned animals was associated with increased astrocytic and microglial branching complexity along the nigrostriatal axis and with a higher proportion of striatal DARPP‑32‑positive MSNs expressing c‑Fos during dopaminergic stimulation, without a change in total c‑Fos‑positive cell counts. These findings indicate that miR‑204‑5p mimic administration can modulate glial morphology and apomorphine‑induced rotational asymmetry in a severely denervated nigrostriatal system without detectable dopaminergic neuroprotection as assessed by TH immunostaining. This exploratory study supports further investigation of glial mechanisms in miR-based approaches to PD.