PINK1 heterozygous mutations induce subtle alterations in dopamine‐dependent synaptic plasticity

Abstract

Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies.

Early synaptic dysfunction in Parkinson's disease: Insights from animal models

“…Particularly, the significant reduction of evoked striatal DA release caused selective impairment of LTP, whereas LTD was physiologically expressed. This evidence suggests that to a different extent PINK1 haploinsufficiency affects the expression of the 2 forms of corticostriatal synaptic plasticity . A similar alteration within the striatal circuitry has been reported in 6‐OHDA partially denervated rodents, as mentioned above .…”

“…Indeed, compelling evidence links either PINK1 gene mutations or mitochondrial dysfunction to the development of PD. The choice of the heterozygous state is of interest, as it may mimic a premanifesting clinical condition and thus reproduce a vulnerable genetic background . Moreover, as described earlier, the subtle plasticity defect, coupled to deficient DA release, is indicative of a vulnerable nigrostriatal synapse, whereas nigral cell viability is preserved.…”

“…Therefore, it is already clear that heterozygous mutations in recessive causative PD genes act as a genetic factor of susceptibility for developing PD . These clinical findings have been translated in the characterization of a mouse model carrying heterozygous PINK1 mutations . Madeo and colleagues have indeed demonstrated that despite the absence of the behavioral phenotype and dopaminergic neuronal loss, early rearrangement within corticostriatal circuitry is occurring in this model, consisting of differential impairment of corticostriatal synaptic plasticity.…”

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

“…This is particularly relevant as 90% of alpha‐synuclein in PD is located presynaptically in much smaller aggregates than Lewy bodies and can be found throughout the brain . Pathologically, alpha‐synuclein, as well as other PD genes and proteins, mainly involve synaptic machinery and play a critical role at the presynaptic site, causing alterations in neurotransmitter reuptake, vesicular storage, and release . Models based on the most prevalent genetic lesions that underlie familial forms of PD, LRRK2 lesions, also have severe neurotransmission defects due to interactions of various presynaptic proteins, including SV2A .…”

Changes in functional organization and white matter integrity in the connectome in Parkinson's disease

“…The highest percentage of alpha-synuclein aggregates in PD are localized at the presynapses. Several other PD-associated proteins (e.g., LRRK2, parkin, DJ-1, PINK1) also alter the dopaminergic presynaptic site (Beccano-Kelly et al, 2015; Kitada et al, 2009; Madeo et al, 2014; Scherfler et al, 2004). The presynaptic changes and depletion of dopamine in turn alter the postsynaptic plasticity (Day et al, 2006).…”