Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.
Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB1R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder.
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Neurological Clinics, Department of Sistems Medicine, Tor Vergata University, 00133 Rome, Italy.
Alessandra
A
Musella
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Neurological Clinics, Department of Sistems Medicine, Tor Vergata University, 00133 Rome, Italy.
Helena
H
Sepman
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Georgia
G
Mandolesi
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Neurological Clinics, Department of Sistems Medicine, Tor Vergata University, 00133 Rome, Italy.
Antonietta
A
Gentile
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Diego
D
Fresegna
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Nabila
N
Haji
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany.
Andrea
A
Conrad
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany.
Beat
B
Lutz
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Center of Integrated Research, School of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy.
Mauro
M
Maccarrone
IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Neurological Clinics, Department of Sistems Medicine, Tor Vergata University, 00133 Rome, Italy. Electronic address: centonze@uniroma2.it.
Diego
D
Centonze
D000818:Animals; D003342:Corpus Striatum / Q000503:physiopathology*; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D043884:Receptor, Cannabinoid, CB1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
EAE; EPSC; Excitotoxicity; GABA; Glutamate; Multiple sclerosis; Striatum