Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.
alpha-Synuclein (alpha-Syn) is a 14 kDa protein of unknown function that has been implicated in the pathophysiology of Parkinson's disease (PD). Here, we show that alpha-Syn-/- mice are viable and fertile, exhibit intact brain architecture, and possess a normal complement of dopaminergic cell bodies, fibers, and synapses. Nigrostriatal terminals of alpha-Syn-/- mice display a standard pattern of dopamine (DA) discharge and reuptake in response to simple electrical stimulation. However, they exhibit an increased release with paired stimuli that can be mimicked by elevated Ca2+. Concurrent with the altered DA release, alpha-Syn-/- mice display a reduction in striatal DA and an attenuation of DA-dependent locomotor response to amphetamine. These findings support the hypothesis that alpha-Syn is an essential presynaptic, activity-dependent negative regulator of DA neurotransmission.
Abeliovich
A
A
Department of Neurology, University of California, San Francisco 94143, USA.
Schmitz
Y
Y
Fariñas
I
I
Choi-Lundberg
D
D
Ho
W H
WH
Castillo
P E
PE
Shinsky
N
N
Verdugo
J M
JM
Armanini
M
M
Ryan
A
A
Hynes
M
M
Phillips
H
H
Sulzer
D
D
Rosenthal
A
A
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000502:physiology; D064026:Calbindins; D002118:Calcium / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D013378:Substantia Nigra / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology; D051843:Synucleins; D051844:alpha-Synuclein; D020826:rab3A GTP-Binding Protein / Q000235:genetics
D017660:Autoreceptors; D064026:Calbindins; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D064030:S100 Calcium Binding Protein G; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D018698:Glutamic Acid; D000661:Amphetamine; D020826:rab3A GTP-Binding Protein; D002118:Calcium; D004298:Dopamine