title: PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity.
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.
authors.affiliation: Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Madeo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Schirinzi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: E Claudio
authors.initials: EC
authors.lastname: Latagliata
authors.forename: Francesca
authors.initials: F
authors.lastname: Puglisi
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Mauro
authors.initials: M
authors.lastname: Federici
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D045442:Rotarod Performance Test; D013378:Substantia Nigra / Q000378:metabolism; D013569:Synapses / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D011494:Protein Kinases; D011954:Receptors, Dopamine; D000099202:PTEN-Induced Putative Kinase
keywords: PINK1; autosomal recessive Parkinson's disease; heterozygous mutations; striatum; synaptic plasticity