Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model

被引：266

作者：

Janezic, Stephanie ^{[1
,2
]}

Threlfell, Sarah ^{[1
,2
]}

Dodson, Paul D. ^{[1
,3
]}

Dowie, Megan J. ^{[1
,3
]}

Taylor, Tonya N. ^{[1
,2
]}

Potgieter, Dawid ^{[1
,2
]}

Parkkinen, Laura ^{[1
,4
]}

Senior, Steven L. ^{[1
,2
]}

Anwar, Sabina ^{[1
,2
]}

Ryan, Brent ^{[1
,2
]}

Deltheil, Thierry ^{[1
,2
]}

Kosillo, Polina ^{[1
,2
]}

Cioroch, Milena ^{[1
,2
]}

Wagner, Katharina ^{[1
,2
]}

Ansorge, Olaf ^{[1
,4
]}

Bannerman, David M. ^{[1
,5
]}

Bolam, J. Paul ^{[1
,3
]}

Magill, Peter J. ^{[1
,3
]}

Cragg, Stephanie J. ^{[1
,2
]}

Wade-Martins, Richard ^{[1
,2
]}

机构：

[1] Univ Oxford, Oxford Parkinsons Dis Ctr, Oxford OX1 3QX, England

[2] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England

[3] Univ Oxford, Dept Pharmacol, Med Res Council Anat Neuropharmacol Unit, Oxford OX1 3QX, England

[4] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX1 3QX, England

[5] Univ Oxford, Dept Expt Psychol, Oxford OX1 3QX, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 42期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

dopamine transmission; in vivo electrophysiology; voltammetry; neurodegeneration; behavioral phenotyping; ALPHA-SYNUCLEIN; SUBSTANTIA-NIGRA; MICE LACKING; CHOLINERGIC INTERNEURONS; LOCUS TRIPLICATION; PARS RETICULATA; GAMMA-SYNUCLEIN; DISEASE; RELEASE; MUTATION;

D O I：

10.1073/pnas.1309143110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type alpha-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous alpha-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.

引用

页码：E4016 / E4025

页数：10

共 32 条

[1]

Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system [J].