Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease.
Cannabinoid CB1 receptors (CB1Rs) are known to be downregulated in patients and in animal models of Huntington's disease (HD). However, the functional meaning of this reduction, if any, is still unclear. Here, the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) were investigated on striatal synaptic transmission and on glutamate and GABA release in symptomatic R6/2 mice, a genetic model of HD. The expression levels of CB1Rs in glutamatergic and GABAergic synapses were also evaluated. We found that in R6/2 mice, WIN effects on synaptic transmission and glutamate release were significantly increased with respect to wild type mice. On the contrary, a decrease in WIN-induced reduction of GABA release was found in R6/2 versus WT mice. The expression of CB1Rs in GABAergic neurons was drastically reduced, while CB1Rs levels in glutamatergic neurons were unchanged. These results demonstrate that the expression and functionality of CB1Rs are differentially affected in GABAergic and glutamatergic neurons in R6/2 mice. As a result, the balance between CB1Rs expressed by the two neuronal populations and, thus, the net effect of CB1R stimulation, is profoundly altered in HD mice.
Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Valentina
V
Chiodi
Motokazu
M
Uchigashima
Sarah
S
Beggiato
Antonella
A
Ferrante
Monica
M
Armida
Alberto
A
Martire
Rosa Luisa
RL
Potenza
Luca
L
Ferraro
Sergio
S
Tanganelli
Masahiko
M
Watanabe
Maria Rosaria
MR
Domenici
Patrizia
P
Popoli
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics; D014316:Tritium / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D048588:Benzoxazines; D018683:Excitatory Amino Acid Agents; D005971:Glutamates; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009025:Morpholines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D014316:Tritium; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C062018:HU 211; D011188:Potassium