title: Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.
abstract: Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK.
authors.affiliation: Hotchkiss Brain Institute and Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and Biology Department, Mount Allison University, Sackville, New Brunswick E4L 1G7, Canada.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Crosby
authors.affiliation: Hotchkiss Brain Institute and Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and.
authors.forename: Dinara V
authors.initials: DV
authors.lastname: Baimoukhametova
authors.affiliation: Hotchkiss Brain Institute and Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and.
authors.forename: Jaideep S
authors.initials: JS
authors.lastname: Bains
authors.affiliation: Hotchkiss Brain Institute and Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and pittman@ucalgary.ca.
authors.forename: Quentin J
authors.identifier: http://orcid.org/0000-0003-0984-7665
authors.initials: QJ
authors.lastname: Pittman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002766:Cholecystokinin / Q000378:metabolism* / Q000494:pharmacology; D004302:Dorsomedial Hypothalamic Nucleus / Q000166:cytology*; D018682:GABA Agents / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050825:Synaptosomal-Associated Protein 25 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C435663:2-(2-(5-bromo-1H-indol-3-yl)ethyl)-3-(1-methylethoxyphenyl)-4-(3H)-quinazolinone; D018682:GABA Agents; D010455:Peptides; D052999:Quinazolinones; D043887:Receptor, Cholecystokinin B; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D013873:Thionucleotides; D006153:Guanosine Diphosphate; D005680:gamma-Aminobutyric Acid; C023427:guanosine 5'-O-(2-thiodiphosphate); D002766:Cholecystokinin; D011377:Proglumide; C048181:lorglumide
keywords: GABA; NMDAR; cholecystokinin; dorsomedial hypothalamus; nitric oxide; somatodendritic release