Journal
MOVEMENT DISORDERS
Volume 29, Issue 1, Pages 41-53Publisher
WILEY-BLACKWELL
DOI: 10.1002/mds.25724
Keywords
PINK1; autosomal recessive Parkinson's disease; heterozygous mutations; synaptic plasticity; striatum
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Funding
- Italian Ministry of Health (Giovani Ricercatori)
- Italian Ministry of Instruction, University, and Research (MIUR) (PRIN)
- Istituto Nazionale Assicurazione contra Infortuni sul Lavoro (INAIL) [2/2009]
- Italian Ministry of Health (Ricerca Corrente)
- Italian Ministry of Health (Ricerca Finalizzata Malattie Rare)
- Italian Telethon Foundation [GGP10140]
- MIUR (FIRB Accordi di Programma)
- National Institutes of Health
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041779] Funding Source: NIH RePORTER
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Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1(+/-) mice compared with 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 normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. 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 Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies. (c) 2013 International Parkinson and Movement Disorder Society
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