INTRODUCTION: Parkinson’s disease (PD) is characterized by late-onset motor symptoms resulting from the loss of dopaminergic neurons (DNs). Increasing evidence suggests that early synaptic and axonal dysfunction—driven by mitochondrial calcium dysregulation and ferroptosis—precedes neuronal death. Previous studies have shown that inhibition of the mitochondrial calcium uniporter (MCU) protects DNs in pink1 mutant models, implicating calcium overload and ferroptosis in the PD. Many of these studies have explored PD using animal models. Zebrafish models offer advantages, including optical transparency, making them well-suited for in vivo studies. Current models and investigations predominantly focus on overt neurodegeneration, often overlooking the critical early phase of synaptic dysfunction.

AIM(S): Given the importance of synaptic dysfunction as an early pathological change in DNs—and the growing interest in using zebrafish models to study PD—our study aims to fill a critical gap by characterizing early physiological changes in PD zebrafish models.

METHOD(S): We aim to characterize the physiological properties of DNs in the periventricular posterior tuberculum (PPt)—a region implicated in PD—by applying local field potential (LFP) recording. This approach enables the detection of altered spike patterns and synaptic latency before the onset of cell loss. We will compare wild-type larvae with both transgenic PD models (pink1, lrrk2) and toxin-induced models (Erastin 5 µM, RSL3 10 µM, Iron 100 µM). Across these models, we will quantify spike amplitude, frequency, and power spectral density. Additionally, we will assess how these parameters change following treatment with the MCU inhibitor Ru360.

RESULTS: Our initial LFP recordings data show a higher frequency of downward spikes with greater amplitude in pink1 mutant 5dpf larvae compared to wild-type, suggesting altered synaptic excitability.

CONCLUSIONS: These findings may reveal early electrophysiological markers of Parkinson’s disease and guide early intervention.

FINANCIAL SUPPORT: This study was supported by the National Science Centre (NCN), OPUS 25, project no. 2023/49/B/NZ4/02744 to JK.