Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling.
Endocannabinoids are crucial for the extinction of aversive memories, a process that considerably involves the amygdala. Here, we show that low-frequency stimulation of afferents in the lateral amygdala with 100 pulses at 1 Hz releases endocannabinoids postsynaptically from neurons of the basolateral amygdala of mice in vitro and thereby induces a long-term depression of inhibitory GABAergic synaptic transmission (LTDi) via a presynaptic mechanism. Lowering inhibitory synaptic transmission significantly increases the amplitude of excitatory synaptic currents in principal neurons of the central nucleus, which is the main output site of the amygdala. LTDi involves a selective mGluR1 (metabotropic glutamate receptor 1)-mediated calcium-independent mechanism and the activation of the adenylyl cyclase-protein kinase A pathway. LTDi is abolished by the cannabinoid type 1 (CB1) receptor antagonist SR141716A and cannot be evoked in CB1 receptor-deficient animals. LTDi is significantly enhanced in mice lacking the anandamide-degrading enzyme fatty acid amide hydrolase. The present findings show for the first time that mGluR activation induces a retrograde endocannabinoid signaling via activation of the adenylyl cyclase-protein kinase A pathway and the release of anandamide. Furthermore, the results indicate that anandamide decreases the activity of inhibitory interneurons in the amygdala. This disinhibition increases the activity of common output neurons and could provide a prerequisite for extinction by formation of new memory.
Azad
Shahnaz C
SC
Clinical Neuropharmacology, Max-Planck-Institute of Psychiatry, 80804 Munich, Germany. azad@mpipsykl.mpg.de
Monory
Krisztina
K
Marsicano
Giovanni
G
Cravatt
Benjamin F
BF
Lutz
Beat
B
Zieglgänsberger
Walter
W
Rammes
Gerhard
G
D000262:Adenylyl Cyclases / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology; D000679:Amygdala / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D063388:Endocannabinoids; D019204:GTP-Binding Proteins / Q000502:physiology; D066298:In Vitro Techniques; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000262:Adenylyl Cyclases; D000581:Amidohydrolases; D002118:Calcium; D063385:Cannabinoid Receptor Modulators; D017868:Cyclic AMP-Dependent Protein Kinases; D063388:Endocannabinoids; D019204:GTP-Binding Proteins; D008071:Lipoprotein Lipase; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; D010738:Type C Phospholipases; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases