title: Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin.
abstract: Compelling evidence supports the important role of the glutamatergic system in the pathophysiology of major depression and also as a target for rapid-acting antidepressants. However, the functional role of glutamate release/transmission in behavioral processes related to depression and antidepressant efficacy remains to be elucidated. In this study, glutamate release and behavioral responses to tail suspension, a procedure commonly used for inducing behavioral despair, were simultaneously monitored in real time. The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset. Blockade of N-methyl-D-aspartic acid (NMDA) receptors by intra-CA3 infusion of MK-801, a non-competitive NMDA receptor antagonist, reversed behavioral despair. A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress. Leptin treatment dampened tail suspension-evoked glutamate release in CA3. On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG. Taken together, these results suggest that the DG-CA3 glutamatergic pathway is critical for mediating behavioral despair and antidepressant-like responses to leptin.
authors.affiliation: 1] Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China [2] Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Lu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology*; D003863:Depression / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D020738:Leptin / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000378:metabolism* / Q000494:pharmacology; D022661:RNA, Untranslated / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics; D014851:Wakefulness
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D020738:Leptin; D022661:RNA, Untranslated; D054411:Receptors, Leptin; D018698:Glutamic Acid; D016202:N-Methylaspartate
references.citation: Hippocampus. 2006;16(3):239-49
references.pmid: 16425236
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E149-58
references.pmid: 24367106
references.citation: Psychopharmacology (Berl). 1985;85(3):367-70
references.pmid: 3923523
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12248-53
references.pmid: 22778410
references.citation: Science. 2001 Mar 30;291(5513):2608-13
references.pmid: 11283374
references.citation: Eur J Neurosci. 2007 May;25(10):3109-14
references.pmid: 17561824
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1593-8
references.pmid: 16423896
references.citation: Mol Psychiatry. 2011 Mar;16(3):252-64
references.pmid: 20661246
references.citation: Nat Neurosci. 2002 May;5(5):405-14
references.pmid: 11953750
references.citation: PLoS One. 2010 Jan 05;5(1):e8566
references.pmid: 20052403
references.citation: Harv Rev Psychiatry. 2010 Sep-Oct;18(5):293-303
references.pmid: 20825266
references.citation: J Cell Sci. 2007 Dec 15;120(Pt 24):4247-60
references.pmid: 18057027
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):830-43
references.pmid: 11063978
references.citation: Nat Rev Neurosci. 2010 Oct;11(10):682-96
references.pmid: 20842175
references.citation: Eur J Neurosci. 2008 May;27(10):2701-13
references.pmid: 18513320
references.citation: J Neurosci. 2005 Mar 30;25(13):3270-9
references.pmid: 15800181
references.citation: Neuron. 2009 May 28;62(4):479-93
references.pmid: 19477151
references.citation: J Neurosci. 2000 Dec 15;20(24):9104-10
references.pmid: 11124987
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12320-2
references.pmid: 11675480
references.citation: Biol Psychiatry. 2003 Sep 1;54(5):499-503
references.pmid: 12946878
references.citation: Nat Neurosci. 2002 Aug;5(8):790-5
references.pmid: 12118256
references.citation: Neurosci Lett. 1988 Jan 22;84(2):131-6
references.pmid: 2893319
references.citation: Nat Neurosci. 2010 Jan;13(1):133-40
references.pmid: 20023653
references.citation: J Neurochem. 2007 May;101(3):815-28
references.pmid: 17250652
references.citation: Arch Gen Psychiatry. 2006 Aug;63(8):856-64
references.pmid: 16894061
references.citation: Brain Res. 1992 Aug 21;588(2):341-5
references.pmid: 1393587
references.citation: Arch Gen Psychiatry. 2010 Aug;67(8):793-802
references.pmid: 20679587
references.citation: Biol Psychiatry. 1999 Dec 1;46(11):1472-9
references.pmid: 10599477
references.citation: Learn Mem. 2007 Nov 14;14(11):705-13
references.pmid: 18007015
references.citation: J Comp Neurol. 1970 Apr;138(4):433-49
references.pmid: 4907846
references.citation: Transl Psychiatry. 2012;2:e83
references.pmid: 22408745
references.citation: J Psychiatry Neurosci. 2004 Nov;29(6):417-26
references.pmid: 15644983
references.citation: J Neuroendocrinol. 2004 Dec;16(12):970-9
references.pmid: 15667452
references.citation: Int J Neuropsychopharmacol. 2013 May;16(4):857-67
references.pmid: 22932068
references.citation: J Neurosci. 2002 Apr 15;22(8):3251-61
references.pmid: 11943826
references.citation: Endocrinology. 2011 Jul;152(7):2634-43
references.pmid: 21521746
references.citation: Pharmacopsychiatry. 1996 Jan;29(1):23-6
references.pmid: 8852530
references.citation: Trends Pharmacol Sci. 2009 Nov;30(11):563-9
references.pmid: 19837463
references.citation: J Neurosci. 2000 Nov 15;20(22):8279-89
references.pmid: 11069934
references.citation: J Comp Neurol. 1978 Oct 15;181(4):681-715
references.pmid: 690280
references.citation: J Neurosci. 1991 Aug;11(8):2321-31
references.pmid: 1908006
references.citation: Mol Psychiatry. 2012 Jul;17(8):790-808
references.pmid: 22182938
references.citation: J Neurochem. 1993 Nov;61(5):1957-60
references.pmid: 7901339
references.citation: Prog Brain Res. 2007;163:697-722
references.pmid: 17765746
references.citation: Biol Psychiatry. 2013 Jun 15;73(12):1133-41
references.pmid: 23726151
references.citation: Neuropharmacology. 2012 Jan;62(1):35-41
references.pmid: 21907221
references.citation: Int J Neuropsychopharmacol. 2011 Jun;14(5):711-7
references.pmid: 20604988
references.citation: Mol Psychiatry. 1996 Sep;1(4):298-9
references.pmid: 9118352
references.citation: Nature. 1977 Apr 21;266(5604):730-2
references.pmid: 559941
references.citation: Curr Opin Pharmacol. 2007 Dec;7(6):648-52
references.pmid: 18032111
references.citation: Synapse. 2000 May;36(2):85-94
references.pmid: 10767055
references.citation: J Comp Neurol. 1975 Jan 15;159(2):149-75
references.pmid: 1112911
references.citation: Biol Psychiatry. 2008 Apr 1;63(7):642-9
references.pmid: 17981266
references.citation: BMC Neurosci. 2013 Jul 29;14:75
references.pmid: 23895555
references.citation: Nature. 2001 Oct 25;413(6858):794-5
references.pmid: 11677594
references.citation: Neuroscience. 1997 Mar;77(1):65-73
references.pmid: 9044375
references.citation: J Comp Neurol. 1986 Apr 22;246(4):435-58
references.pmid: 3700723
references.citation: J Neurosci. 1998 May 1;18(9):3386-403
references.pmid: 9547246
references.citation: Neurol Res. 2011 Nov;33(9):899-907
references.pmid: 22080989
references.citation: Neuroscience. 2011 Feb 3;174:26-36
references.pmid: 21108993
references.citation: Nat Rev Neurosci. 2011 Nov 30;13(1):22-37
references.pmid: 22127301
references.citation: Biol Psychiatry. 2000 Feb 15;47(4):351-4
references.pmid: 10686270
references.citation: Br J Pharmacol. 2010 Jun;160(4):785-809
references.pmid: 20136842
references.citation: Hippocampus. 2003;13(1):133-49
references.pmid: 12625464
references.citation: Nat Med. 1998 Nov;4(11):1313-7
references.pmid: 9809557
references.citation: Neurochem Res. 2010 May;35(5):693-701
references.pmid: 20069359
references.citation: Trends Neurosci. 2003 Nov;26(11):631-40
references.pmid: 14585604
references.citation: Med Hypotheses. 2011 Oct;77(4):508-28
references.pmid: 21741771
references.citation: J Neurochem. 1995 Jul;65(1):268-74
references.pmid: 7790870
references.citation: Neuron. 2004 Feb 5;41(3):445-54
references.pmid: 14766182
references.citation: J Physiol. 2008 Mar 15;586(6):1495-502
references.pmid: 18079156
references.citation: J Clin Psychopharmacol. 2008 Dec;28(6):631-7
references.pmid: 19011431
references.citation: Annu Rev Neurosci. 1999;22:105-22
references.pmid: 10202533
references.citation: Brain Res. 1985 Feb 11;326(2):251-60
references.pmid: 2982461
references.citation: Restor Neurol Neurosci. 1997 Jan 1;11(3):153-60
references.pmid: 21551539
references.citation: Am J Psychiatry. 2002 Jul;159(7):1112-8
references.pmid: 12091188
references.citation: J Comp Neurol. 1990 Nov 15;301(3):365-81
references.pmid: 2262596
references.citation: Mol Psychiatry. 2011 Oct;16(10):1024-38
references.pmid: 21483433
references.citation: Neurochem Res. 2011 May;36(5):793-800
references.pmid: 21253855
references.citation: J Neurochem. 1993 May;60(5):1650-7
references.pmid: 8097232
references.citation: J Neurosci. 2013 May 1;33(18):7770-7
references.pmid: 23637169