Early bioenergetic changes and altered neuronal excitability in a rodent model of prodromal Parkinson's disease

Parkinson’s disease (PD) is closely related to mitochondrial dysfunction, but it is unclear how early metabolic alterations affect neuronal function before obvious neurodegeneration. We investigated male PTEN-induced kinase 1 mice at postnatal days 30 and 60 using a multidisciplinary approach integrating behavioural, proteomic, bioenergetic, skeletal-muscle and electrophysiological analyses. Motor performance showed subtle age-dependent alterations, whereas sensorimotor function remained largely preserved despite age- and region-dependent molecular remodelling within the nigrostriatal system. On postnatal day 60, dorsal striatal tissue showed increased respiratory reserve, while skeletal muscle developed a more oxidative phenotype. In parallel, striatal neurons showed age-dependent hypoexcitability with a Glibenclamide-sensitive component, whereas nigral dopaminergic neurons showed altered depolarisation-evoked Ca²⁺ responses. These findings indicate that early PINK1 deficiency is characterised by age- and region-dependent metabolic and functional adaptation rather than generalised mitochondrial failure, consistent with bioenergetic remodelling as a feature of early PINK1-associated pathology