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

Graziella Madeo, Tommaso Schirinzi, Giuseppina Martella, E. Claudio Latagliata, Francesca Puglisi, Jie Shen, Enza Maria Valente, Mauro Federici, Nicola B. Mercuri, Stefano Puglisi-Allegra, Paola Bonsi, Antonio Pisani

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)41-53
Number of pages13
JournalMovement Disorders
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Neuronal Plasticity
Long-Term Potentiation
Dopamine
Corpus Striatum
Mutation
Endophenotypes
Monoamine Oxidase Inhibitors
Dopaminergic Neurons
Monoamine Oxidase
Dopamine Receptors
Parkinsonian Disorders
Substantia Nigra
Heterozygote
Phosphoric Monoester Hydrolases
Knockout Mice
Parkinson Disease
Phosphotransferases
Pharmacology
Depression
Neurons

Keywords

  • Autosomal recessive Parkinson's disease
  • Heterozygous mutations
  • PINK1
  • Striatum
  • Synaptic plasticity

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. / Madeo, Graziella; Schirinzi, Tommaso; Martella, Giuseppina; Latagliata, E. Claudio; Puglisi, Francesca; Shen, Jie; Valente, Enza Maria; Federici, Mauro; Mercuri, Nicola B.; Puglisi-Allegra, Stefano; Bonsi, Paola; Pisani, Antonio.

In: Movement Disorders, Vol. 29, No. 1, 01.2014, p. 41-53.

Research output: Contribution to journalArticle

Madeo G, Schirinzi T, Martella G, Latagliata EC, Puglisi F, Shen J et al. PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. Movement Disorders. 2014 Jan;29(1):41-53. https://doi.org/10.1002/mds.25724
Madeo, Graziella ; Schirinzi, Tommaso ; Martella, Giuseppina ; Latagliata, E. Claudio ; Puglisi, Francesca ; Shen, Jie ; Valente, Enza Maria ; Federici, Mauro ; Mercuri, Nicola B. ; Puglisi-Allegra, Stefano ; Bonsi, Paola ; Pisani, Antonio. / PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. In: Movement Disorders. 2014 ; Vol. 29, No. 1. pp. 41-53.
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