Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others.
Cholecystokinin (CCK) is the most abundant neuropeptide in the central nervous system. In the hippocampal CA1 region, CCK is co-localized with GABA in a subset of interneurons that synapse on pyramidal cell somata and apical dendrites. CCK-containing interneurons also uniquely express a high level of the cannabinoid receptor, CB(1), and mediate the retrograde signaling process called DSI. Reported effects of CCK on inhibitory post-synaptic potentials (IPSPs) in hippocampus are inconsistent, and include both increases and decreases in activity. Hippocampal interneurons are very heterogeneous, and these results could be reconciled if CCK affected different interneurons in different ways. To test this prediction, we used sharp microelectrode recordings from pyramidal cells with ionotropic glutamate receptors blocked, and investigated the effects of CCK on pharmacologically distinct groups of IPSPs during long-term recordings. We find that CCK, acting via the CCK(2) receptor, increases some IPSPs and decreases others, and most significantly, that the affected IPSPs can be classified into two groups by their pharmacological properties. IPSPs that are increased by carbachol (CCh-sIPSPs), are depressed by CCK, omega-conotoxin GVIA, and endocannabinoids. IPSPs that are enhanced by CCK (CCK-sIPSPs) are blocked by omega-agatoxin IVA, and are unaffected by carbachol or endocannabinoids. Interestingly, a CCK(2) antagonist enhances CCh-sIPSPs, suggesting normally they may be partially suppressed by endogenous CCK. In summary, our data are compatible with the hypothesis that CCK has opposite actions on sIPSPs that originate from functionally distinct interneurons.
Karson
Miranda A
MA
Department of Physiology, Program in Neuroscience, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
Whittington
Kevin C
KC
Alger
Bradley E
BE
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D063388:Endocannabinoids; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008954:Models, Biological; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology
D000779:Anesthetics, Local; D063385:Cannabinoid Receptor Modulators; D018679:Cholinergic Agonists; D063388:Endocannabinoids; D013779:Tetrodotoxin; D002217:Carbachol; D002766:Cholecystokinin
J Neurosci. 1998 Aug 1;18(15):5640-51
9671655
J Physiol. 1990 Nov;430:213-49
1707966
Neuroscience. 1998 Mar;83(2):393-411
9460749
J Neurosci. 1992 Oct;12(10):4122-32
1403103
Trends Neurosci. 2003 Sep;26(9):489-95
12948660
Neuropeptides. 1988 Aug-Sep;12(2):95-103
2847075
Trends Neurosci. 2004 Mar;27(3):135-42
15036878
J Physiol. 1996 Oct 1;496 ( Pt 1):197-209
8910208
J Neurosci Methods. 1981 Aug;4(2):153-6
7278366
Neuroscience. 1997 Jun;78(4):1005-16
9174069
J Neurochem. 1985 Jan;44(1):1-10
2856882
Neuron. 1993 Feb;10(2):165-75
7679913
J Neurosci. 1997 Jul 1;17(13):4994-5003
9185537
J Neurosci. 1984 Oct;4(10):2590-603
6149275
J Physiol. 2005 Jan 1;562(Pt 1):81-8
15528238
J Neurophysiol. 2004 Oct;92(4):2105-12
15175370
J Neurophysiol. 1995 Sep;74(3):990-1000
7500167
J Neurosci Res. 2005 Feb 1;79(3):412-20
15605383
Nature. 1998 Jul 9;394(6689):186-9
9671302
Neuron. 2002 Jan 31;33(3):325-40
11832222
Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1130-3
1996314
J Neurosci. 1999 Jun 1;19(11):4544-58
10341254
J Physiol. 1979 Oct;295:61P-62P
521978
J Physiol. 2001 May 1;532(Pt 3):685-700
11313439
Nature. 1976 Dec 9;264(5586):568-70
63918
J Neurosci. 1999 Oct 1;19(19):8637-45
10493764
J Pharmacol Exp Ther. 1994 Feb;268(2):753-61
8113987
J Neurochem. 1999 Nov;73(5):1973-81
10537055
J Neurosci. 1999 Jul 15;19(14):5693-702
10407010
Brain Res. 1988 Jun 7;451(1-2):309-18
3251590
Neuropharmacology. 2004 Sep;47(3):381-9
15275827
Nature. 1995 Nov 2;378(6552):75-8
7477292
Neuroscience. 1999;92(1):61-71
10392830
Nature. 2001 Mar 29;410(6828):588-92
11279497
J Physiol. 2002 Mar 15;539(Pt 3):857-68
11897855
Neuron. 2003 Jun 5;38(5):805-17
12797964
Proc Natl Acad Sci U S A. 1979 Jan;76(1):521-5
284371
Trends Neurosci. 2003 Dec;26(12):676-82
14624852
J Physiol. 1998 Oct 1;512 ( Pt 1):61-73
9729617
Neurosci Lett. 2000 Nov 3;293(3):167-70
11036187
Eur J Pharmacol. 1993 Dec 21;250(3):423-30
8112402
Neuropharmacology. 1997 Mar;36(3):389-96
9175618
J Neurosci. 2000 Apr 1;20(7):2470-9
10729327
Nat Neurosci. 2005 Oct;8(10):1319-28
16158066
Eur J Neurosci. 2004 May;19(10):2682-92
15147302
Brain Res. 1981 May 11;212(1):51-7
7225864
Eur J Neurosci. 1999 Dec;11(12):4213-25
10594647
Brain Res. 1987 Mar 17;406(1-2):130-5
3032354
Hippocampus. 1996;6(4):347-470
8915675
J Physiol. 1992 May;450:127-42
1359121
J Neurosci. 1998 Feb 15;18(4):1305-17
9454840
Eur J Neurosci. 1992;4(6):563-573
12106342
Neuron. 2001 Aug 16;31(3):453-62
11516401
Neuron. 1997 Mar;18(3):463-72
9115739
J Neurosci. 1983 Apr;3(4):877-906
6300358
J Comp Neurol. 2002 Feb 18;443(4):346-67
11807843
J Physiol. 2002 Sep 15;543(Pt 3):779-93
12231638
J Neurophysiol. 2005 Dec;94(6):4290-9
16093334
J Neurosci. 2001 Dec 15;21(24):RC188
11734603
Neuroscience. 1997 Aug;79(3):629-48
9219929
Nat Neurosci. 2006 Jun;9(6):807-15
16648849
J Physiol. 2006 Apr 15;572(Pt 2):425-42
16455686