Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system

Neuron. 2000 Jan;25(1):239-52. doi: 10.1016/s0896-6273(00)80886-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Autoreceptors / physiology
  • Calbindins
  • Calcium / pharmacokinetics
  • Corpus Striatum / chemistry
  • Corpus Striatum / cytology
  • Corpus Striatum / physiopathology*
  • Dopamine / analysis
  • Dopamine / metabolism*
  • Dopamine Agents / pharmacology
  • Female
  • Gene Expression / physiology
  • Glutamic Acid / physiology
  • Hippocampus / chemistry
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Locomotion / drug effects
  • Locomotion / genetics
  • Long-Term Potentiation / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Nerve Tissue Proteins / genetics*
  • Neurons / chemistry
  • Neurons / physiology
  • Presynaptic Terminals / chemistry
  • Presynaptic Terminals / metabolism
  • S100 Calcium Binding Protein G / analysis
  • Substantia Nigra / chemistry
  • Substantia Nigra / cytology
  • Substantia Nigra / physiopathology*
  • Synaptic Transmission / physiology
  • Synucleins
  • alpha-Synuclein
  • rab3A GTP-Binding Protein / genetics

Substances

  • Autoreceptors
  • Calbindins
  • Dopamine Agents
  • Nerve Tissue Proteins
  • S100 Calcium Binding Protein G
  • Snca protein, mouse
  • Synucleins
  • alpha-Synuclein
  • Glutamic Acid
  • Amphetamine
  • rab3A GTP-Binding Protein
  • Calcium
  • Dopamine