These authors contributed equally to this work.
PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity
Article first published online: 25 OCT 2013
Copyright © 2013 Movement Disorder Society
Volume 29, Issue 1, pages 41–53, January 2014
How to Cite
Madeo, G., Schirinzi, T., Martella, G., Latagliata, E. C., Puglisi, F., Shen, J., Valente, E. M., Federici, M., Mercuri, N. B., Puglisi-Allegra, S., Bonsi, P. and Pisani, A. (2014), PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. Mov. Disord., 29: 41–53. doi: 10.1002/mds.25724
Funding agencies: This study was supported by grants from the Italian Ministry of Health (Giovani Ricercatori 2009), the Italian Ministry of Instruction, University, and Research (MIUR) (PRIN 2011), and the Istituto Nazionale Assicurazione contro Infortuni sul Lavoro (INAIL, project 2/2009) to A.P.; by grants from the Italian Ministry of Health (Ricerca Corrente 2013, Ricerca Finalizzata Malattie Rare 2008, and Giovani Ricercatori 2009), the Italian Telethon Foundation (GGP10140), and MIUR (FIRB Accordi di Programma 2010) to E.M.V.; and by grant NS 041779 from the National Institutes of Health to J.S.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
- Issue published online: 23 JAN 2014
- Article first published online: 25 OCT 2013
- Manuscript Accepted: 16 SEP 2013
- Manuscript Revised: 10 SEP 2013
- Manuscript Received: 23 APR 2013
- autosomal recessive Parkinson's disease;
- heterozygous mutations;
- synaptic plasticity;
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. © 2013 International Parkinson and Movement Disorder Society