Neuregulin-1 impairs the long-term depression of hippocampal inhibitory synapses by facilitating the degradation of endocannabinoid 2-AG.
Endocannabinoids play essential roles in synaptic plasticity; thus, their dysfunction often causes impairments in memory or cognition. However, it is not well understood whether deficits in the endocannabinoid system account for the cognitive symptoms of schizophrenia. Here, we show that endocannabinoid-mediated synaptic regulation is impaired by the prolonged elevation of neuregulin-1, the abnormality of which is a hallmark in many patients with schizophrenia. When rat hippocampal slices were chronically treated with neuregulin-1, the degradation of 2-arachidonoylglycerol (2-AG), one of the major endocannabinoids, was enhanced due to the increased expression of its degradative enzyme, monoacylglycerol lipase. As a result, the time course of depolarization-induced 2-AG signaling was shortened, and the magnitude of 2-AG-dependent long-term depression of inhibitory synapses was reduced. Our study reveals that an alteration in the signaling of 2-AG contributes to hippocampal synaptic dysfunction in a hyper-neuregulin-1 condition and thus provides novel insights into potential schizophrenic therapeutics that target the endocannabinoid system.
Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
Huizhi
H
Du
In-Kiu
IK
Kwon
Jimok
J
Kim
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001703:Biophysics; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D020890:Neuregulin-1 / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*
C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D020890:Neuregulin-1; D010880:Piperidines; D011743:Pyrimidines; D043884:Receptor, Cannabinoid, CB1; D008734:Methoxyhydroxyphenylglycol; C094503:glyceryl 2-arachidonate; C010117:3,4-dihydroxyphenylglycol; C107594:N-(4-hydroxyphenyl)arachidonylamide