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Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice

Kitada, Tohru ; Pisani, Antonio ; Porter, Douglas R ; Yamaguchi, Hiroo ; Tscherter, Anne ; Martella, Giuseppina ; Bonsi, Paola ; Zhang, Chen ; Pothos, Emmanuel N ; Shen, Jie

Proceedings of the National Academy of Sciences - PNAS, 2007-07, Vol.104 (27), p.11441-11446 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice
Autor: Kitada, Tohru ; Pisani, Antonio ; Porter, Douglas R ; Yamaguchi, Hiroo ; Tscherter, Anne ; Martella, Giuseppina ; Bonsi, Paola ; Zhang, Chen ; Pothos, Emmanuel N ; Shen, Jie
Assuntos: Agonists ; Animals ; Biological Sciences ; Brain ; Catecholamines ; Cells, Cultured ; Chromaffin cells ; Corpus Striatum - enzymology ; Corpus Striatum - pathology ; Dopamine - secretion ; Exons ; Kinases ; Long term depression ; Long term potentiation ; Long-Term Synaptic Depression - genetics ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Molecules ; Neuronal Plasticity - genetics ; Neurons ; Neurotransmitters ; Parkinson disease ; Parkinson Disease - enzymology ; Parkinson Disease - genetics ; Parkinson's disease ; Presynaptic Terminals - enzymology ; Presynaptic Terminals - physiology ; Protein Kinases - deficiency ; Protein Kinases - genetics ; Protein Kinases - physiology ; Receptors ; Rodents
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2007-07, Vol.104 (27), p.11441-11446
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 1, 2007
Author contributions: A.P., E.N.P., and J.S. designed research; T.K., D.R.P., H.Y., A.T., G.M., P.B., and C.Z. performed research; T.K., A.P., H.Y., C.Z., E.N.P., and J.S. analyzed data; and A.P., E.N.P., and J.S. wrote the paper.
Descrição: Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1⁻/⁻ mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1⁻/⁻ mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1⁻/⁻ mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice

Kitada, Tohru ; Pisani, Antonio ; Porter, Douglas R ; Yamaguchi, Hiroo ; Tscherter, Anne ; Martella, Giuseppina ; Bonsi, Paola ; Zhang, Chen ; Pothos, Emmanuel N ; Shen, Jie

United States: National Academy of Sciences

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