Dopamine-dependent CB1 receptor dysfunction at corticostriatal synapses in homozygous PINK1 knockout mice.
Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (PD). We investigated the interaction between endocannabinoid (eCB) and dopaminergic transmission at corticostriatal synapses in PINK1 deficient mice. Whole-cell patch-clamp and conventional recordings of striatal medium spiny neurons (MSNs) were made from slices of PINK1(-/-), heterozygous PINK1(+/-) mice and wild-type littermates (PINK1(+/+)). In PINK1(+/+) mice, CB1 receptor (CB1R) activation reduced spontaneous excitatory postsynaptic currents (sEPSCs). Likewise, CB1R agonists (ACEA, WIN55,212-3 and HU210) induced a dose-dependent reduction of cortically-evoked excitatory postsynaptic potential (eEPSP) amplitude. While CB1R agonists retained their inhibitory effect in heterozygous PINK1(+/-) mice, conversely, in PINK1(-/-) mice they failed to modulate sEPSC amplitude. Similarly, CB1R activation failed to reduce eEPSP amplitude in PINK1(-/-) mice. Parallel biochemical measurements revealed no significant difference in the levels of the two main eCBs, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) in PINK1(-/-) striata. Similarly, no change was observed in the enzymatic activity of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), responsible for eCB hydrolysis. Instead, a significant reduction of binding ability of CB1R agonists was found in PINK1(-/-) mice. Notably, the CB1R-dependent inhibition of synaptic activity was restored either by amphetamine or after chronic treatment with the D2 dopamine receptor agonist quinpirole. Additionally, CB1R binding activity returned to control levels after chronic pretreatment with quinpirole. Consistent with the hypothesis of a close interplay with dopaminergic neurotransmission, our findings show a CB1R dysfunction at corticostriatal synapses in PINK1(-/-), but not in PINK1(+/-) mice, and provide a mechanistic link to the distinct plasticity deficits observed in both genotypes.
Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy.
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Madeo
Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy.
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Schirinzi
Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy.
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Maltese
Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy.
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Martella
Faculty of Veterinary Medicine, University of Teramo, Italy.
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Rapino
Department of Experimental Medicine & Surgery, University of Rome, "Tor Vergata", Rome, Italy; Fondazione Santa Lucia, IRCCS, Rome, Italy.
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Fezza
School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy.
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Mastrangelo
Fondazione Santa Lucia, IRCCS, Rome, Italy.
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Bonsi
Fondazione Santa Lucia, IRCCS, Rome, Italy; School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy.
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Maccarrone
Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy; Fondazione Santa Lucia, IRCCS, Rome, Italy. Electronic address: pisani@uniroma2.it.
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Pisani
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D003342:Corpus Striatum / Q000166:cytology*; D003511:Cyclohexanols / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D000099202:PTEN-Induced Putative Kinase
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D003511:Cyclohexanols; D004298:Dopamine; D015259:Dopamine Agents; D013759:Dronabinol; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D009025:Morpholines; D009281:Naphthalenes; D011494:Protein Kinases; D043884:Receptor, Cannabinoid, CB1; D014316:Tritium; D000099202:PTEN-Induced Putative Kinase; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C062018:HU 211
Dopamine; Electrophysiology; Endocannabinoid; PINK1; Parkinson's disease; Striatum