Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Abstract

Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. Synapse 70:223-230,

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

“…Mildly significant was the enrichment of 21 factors of the “Dopaminergic synapse” pathway ( q value 0.005), 16 factors of the “GABAergic synapse” pathway ( q value 0.008), and 18 factors of the “Glutamatergic pathway” pathway ( q value 0.015). These data are in excellent consistency with previously established roles of PINK1 as a component of MAPK signaling [ 51 , 52 ], as an activator of PARKIN which prevents bacterial invasions [ 18 ], and as a modifier of dopaminergic, GABAergic, and glutamatergic signaling in the nigrostriatal pathway [ 44 , 53 – 56 ]. The agreement of our bioinformatics analysis of the global transcriptome with previously published cell biology data provides credibility to this automated approach.…”

Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus

“…Because other factors, in particular exercise and stress hormone levels, are known to affect neurogenesis, we studied whether loss of PINK1 caused changes in home cage activity and corticosterone levels of mice; however, neither was the case, which ruled out that decreased physical activity and/or increased stress hormone levels, in part, were responsible for neurogenesis defects of PINK1 2/2 mice. We cannot entirely exclude that a subtle change in excitatory neurotransmission in the hippocampus of PINK1 2/2 mice (61) may have influenced neurogenesis in our studies; however, we note that the reported alterations in glutamate release were without effect on hippocampal long-term potentiation (61), which was in agreement with a previous work that showed normal basal neurotransmission and synaptic plasticity in the hippocampus of PINK1 2/2 mice (62). In addition to exogenous factors, ROS affect neurogenesis and are implicated in the pathogenesis of many neurodegenerative disorders, including PD and Alzheimer's disease (63,64).…”

Monitoring of glutamate‐induced excitotoxicity by mitochondrial oxygen consumption

“…Mitochondrial activity is important for energy supply in neurons, and mitochondrial dysfunctions is thought to lead to neurodegenerative diseases, including Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). These are intractable disorders characterized by irreversible loss of neurons (Devine & Kittler, 2018;Feligioni et al, 2016;Islam, 2017;Smith, Shaw, & De Vos, 2017). Despite their differences in pathophysiological features and cell-types specificities, impairment of energy metabolism associated with mitochondrial failure is often observed in these diseases, e.g., dysfunctions of NADH-ubiquinone reductase (also called as mitochondrial complex I) in PD (Schapira et al, 1989), and succinate dehydrogenase (mitochondrial complex II) in HD (Miller & Zaborszky, 1997), and axonal transport of mitochondria in ALS (Moller, Bauer, Cohen, Webster, & Vos, 2017).…”