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

• Published in: Neurobiology of disease Vol. 68; pp. 190 - 199
• Main Authors: Chou, Jun-Shiao, Chen, Chu-Yu, Chen, Ying-Ling, Weng, Yi-Hsin, Yeh, Tu-Hsueh, Lu, Chin-Song, Chang, Ya-Ming, Wang, Hung-Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2014; Elsevier
• Subjects: (G2019S) LRRK2; (G2019S) LRRK2 transgenic mouse; Animals; Apomorphine - pharmacology; Cerebral Cortex - physiopathology; Corpus Striatum - physiopathology; Corticostriatal long-term depression; Corticostriatal long-term potentiation; Dopamine Agonists - pharmacology; Dopaminergic Neurons - physiology; Evoked dopamine release; 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; Neurology; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Picrotoxin - pharmacology; Protein-Serine-Threonine Kinases - genetics; Radionuclide Imaging; Serine - genetics; SNpc dopaminergic neurons; Striatal medium spiny neurons; Substantia Nigra - diagnostic imaging; Substantia Nigra - pathology; Tyrosine 3-Monooxygenase - metabolism; (G2019S) LRRK2; Evoked dopamine release; (G2019S) LRRK2 transgenic mouse; Striatal medium spiny neurons; SNpc dopaminergic neurons; Corticostriatal long-term depression; Corticostriatal long-term potentiation
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.04.021

Abstract 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 9 months 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.