Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease

Alessandro Tozzi, Valentina Durante, Guendalina Bastioli, Petra Mazzocchetti, Salvatore Novello, Alessandro Mechelli, Michele Morari, Cinzia Costa, Andrea Mancini, Massimiliano Di Filippo, Paolo Calabresi

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Abstract

Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalNeurobiology of Disease
Volume118
DOIs
Publication statusPublished - Oct 1 2018

Fingerprint

Corpus Striatum
Dopamine D2 Receptors
Genetic Models
Leucine
Parkinson Disease
Quinpirole
Phosphotransferases
Synaptic Transmission
Mutation
Excitatory Postsynaptic Potentials
Neurons
Knockout Mice
Presynaptic Receptors
Cannabinoid Receptors
Endocannabinoids
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Dopamine Agonists
Type C Phospholipases
Missense Mutation
N-Methylaspartate

Keywords

  • Dopamine
  • Electrophysiology
  • Lrrk2
  • Mouse model
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology

Cite this

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease. / Tozzi, Alessandro; Durante, Valentina; Bastioli, Guendalina; Mazzocchetti, Petra; Novello, Salvatore; Mechelli, Alessandro; Morari, Michele; Costa, Cinzia; Mancini, Andrea; Di Filippo, Massimiliano; Calabresi, Paolo.

In: Neurobiology of Disease, Vol. 118, 01.10.2018, p. 1-8.

Research output: Contribution to journalArticle

Tozzi, A, Durante, V, Bastioli, G, Mazzocchetti, P, Novello, S, Mechelli, A, Morari, M, Costa, C, Mancini, A, Di Filippo, M & Calabresi, P 2018, 'Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease', Neurobiology of Disease, vol. 118, pp. 1-8. https://doi.org/10.1016/j.nbd.2018.06.008
Tozzi, Alessandro ; Durante, Valentina ; Bastioli, Guendalina ; Mazzocchetti, Petra ; Novello, Salvatore ; Mechelli, Alessandro ; Morari, Michele ; Costa, Cinzia ; Mancini, Andrea ; Di Filippo, Massimiliano ; Calabresi, Paolo. / Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease. In: Neurobiology of Disease. 2018 ; Vol. 118. pp. 1-8.
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