(G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse

Neurobiol Dis. 2014 Aug:68:190-9. doi: 10.1016/j.nbd.2014.04.021. Epub 2014 May 14.


Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive neuronal death of substantia nigra pars compacta (SNpc) dopaminergic cells. In the present study, we hypothesized that prior to a late-phase death of SNpc dopaminergic neurons, (G2019S) LRRK2 also causes an early-phase neuronal dysfunction of SNpc dopaminergic cells in the (G2019S) LRRK2 mouse. Eight to nine-month-old (G2019S) LRRK2 transgenic mice exhibited the symptom of hypoactivity in the absence of the degeneration of SNpc dopaminergic neurons or nigrostriatal dopaminergic terminals. Whole-cell current-clamp recordings of SNpc dopaminergic cells in brain slices demonstrated a significant decrease in spontaneous firing frequency of SNpc dopaminergic neurons of 8-month-old (G2019S) LRRK2 mice. Carbon fiber electrode amperometry recording using striatal slices showed that (G2019S) LRRK2 transgenic mice at the age of 8 to 9months display an impaired evoked dopamine release in the dorsolateral striatum. Normal nigrostriatal dopaminergic transmission is required for the induction of long-term synaptic plasticity expressed at corticostriatal glutamatergic synapses of striatal medium spiny neurons. Whole-cell voltage-clamp recordings showed that in contrast to medium spiny neurons of 8 to 9-month-old wild-type mice, high-frequency stimulation of corticostriatal afferents failed to induce long-term depression (LTD) of corticostriatal EPSCs in medium spiny neurons of (G2019S) LRRK2 mice at the same age. Our study provides the evidence that mutant (G2019S) LRRK2 causes early-phase dysfunctions of SNpc dopaminergic neurons, including a decrease in spontaneous firing rate and a reduction in evoked dopamine release, and impairment of corticostriatal LTD in the (G2019S) LRRK2 transgenic mouse.

Keywords: (G2019S) LRRK2; (G2019S) LRRK2 transgenic mouse; Corticostriatal long-term depression; Corticostriatal long-term potentiation; Evoked dopamine release; SNpc dopaminergic neurons; Striatal medium spiny neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apomorphine / pharmacology
  • Cerebral Cortex / physiopathology
  • Corpus Striatum / physiopathology
  • Dopamine Agonists / pharmacology
  • Dopaminergic Neurons / physiology*
  • GABA Antagonists / pharmacology
  • Glycine / genetics
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics*
  • Mice
  • Mice, Transgenic
  • Motor Activity / genetics
  • Mutation / genetics*
  • Parkinson Disease* / genetics
  • Parkinson Disease* / pathology
  • Parkinson Disease* / physiopathology
  • Picrotoxin / pharmacology
  • Protein Serine-Threonine Kinases / genetics*
  • Radionuclide Imaging
  • Serine / genetics
  • Substantia Nigra / diagnostic imaging
  • Substantia Nigra / pathology*
  • Tyrosine 3-Monooxygenase / metabolism


  • Dopamine Agonists
  • GABA Antagonists
  • Picrotoxin
  • Serine
  • Tyrosine 3-Monooxygenase
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • Apomorphine
  • Glycine