Abnormal sensitivity to cannabinoid receptor stimulation might contribute to altered gamma-aminobutyric acid transmission in the striatum of R6/2 Huntington's disease mice.
BACKGROUND
One of the earliest neurochemical alterations observed in both Huntington's disease (HD) patients and HD animal models is the dysregulation of the endocannabinoid system, an alteration that precedes the development of identifiable striatal neuropathology. How this alteration impacts striatal synaptic transmission is unknown.


METHODS
We measured the effects of cannabinoid receptor stimulation on gamma-aminobutyric acid (GABA)-ergic synaptic currents recorded from striatal neurons of R6/2 HD mice in the early phase of their disease.


RESULTS
The sensitivity of striatal GABA synapses to cannabinoid receptor stimulation is severely impaired in R6/2 HD mice. In particular, whereas in control animals activation of cannabinoid CB1 receptors results in a significant inhibition of both evoked and spontaneous GABA-mediated synaptic events by a presynaptic mechanism, in R6/2 mice this treatment fails to reduce GABA currents but causes, in contrast, a slight increase of spontaneous inhibitory postsynaptic currents (sIPSCs).


CONCLUSIONS
Experimental HD was also associated with enhanced frequency of sIPSCs, a result consistent with the conclusion that loss of cannabinoid-mediated control of GABA transmission might contribute to hyperactivity of GABA synapses in the striatum of HD mice. Accordingly, spontaneous excitatory postsynaptic currents, which were not upregulated in R6/2 mice, were still sensitive to cannabinoid receptor stimulation.
Centonze
Diego
D
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Tor Vergata, Italy. centonze@uniroma2.it
Rossi
Silvia
S
Prosperetti
Chiara
C
Tscherter
Anne
A
Bernardi
Giorgio
G
Maccarrone
Mauro
M
Calabresi
Paolo
P
D000818:Animals; D000831:Animals, Newborn; D063387:Cannabinoid Receptor Antagonists; D003342:Corpus Striatum / Q000378:metabolism*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006816:Huntington Disease / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000502:physiology*; D000077285:Rimonabant; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D063387:Cannabinoid Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D005680:gamma-Aminobutyric Acid; D000077285:Rimonabant