(G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse.
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.
Department of Physiology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC.
Jun-Shiao
JS
Chou
Department of Physiology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC.
Chu-Yu
CY
Chen
Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan, Taiwan, ROC.
Ying-Ling
YL
Chen
Department of Neurology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC.
Yi-Hsin
YH
Weng
Department of Neurology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC.
Tu-Hsueh
TH
Yeh
Department of Neurology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC.
Chin-Song
CS
Lu
Department of Physiology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC; Graduate Institute of Biomedical Sciences, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC.
Ya-Ming
YM
Chang
Department of Physiology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC. Electronic address: hlwns@mail.cgu.edu.tw.
Hung-Li
HL
Wang
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000503:physiopathology; D003342:Corpus Striatum / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010852:Picrotoxin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011877:Radionuclide Imaging; D012694:Serine / Q000235:genetics; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001058:Apomorphine; D018491:Dopamine Agonists; D018756:GABA Antagonists; D005998:Glycine; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010852:Picrotoxin; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human
(G2019S) LRRK2; (G2019S) LRRK2 transgenic mouse; Corticostriatal long-term depression; Corticostriatal long-term potentiation; Evoked dopamine release; SNpc dopaminergic neurons; Striatal medium spiny neurons