title: NMDA receptors increase the size of GABAergic terminals and enhance GABA release.
abstract: In developing cerebellar interneurons, NMDA increases spontaneous GABA release by activating presynaptic NMDA receptors. We investigated the role of these receptors on differentiating basket/stellate cells in cerebellar cultures grown under conditions allowing functional synaptic transmission. Presynaptic GABAergic boutons were visualized either by GAD65 immunostaining or by using cells derived from GAD65-enhanced green fluorescent protein (eGFP) transgenic mice, in which cerebellar basket/stellate cells express eGFP. After the first week in culture, whole-cell recordings from granule cells reveal that acute application of NMDA increases miniature IPSC (mIPSC) frequency. Interestingly, after 2 weeks, the mIPSC frequency increases compared with the first week but is not modulated by NMDA. Furthermore, in cultures chronically treated with NMDA for 1 week, the size of the GABAergic boutons increases. This growth is paralleled by increased mIPSC frequency and the loss of NMDA sensitivity. Direct patch-clamp recording from these presynaptic terminals reveals single NMDA-activated channels, showing multiple conductance levels, and electronic propagation from the somatodendritic compartment. Our results demonstrate that NMDA receptors alter GABAergic synapses in developing cerebellar cultures by increasing the size of the terminal and spontaneous GABA release. These findings parallel changes in inhibitory synaptic efficacy seen in vivo in developing GABAergic interneurons of the molecular layer of the cerebellum.
authors.affiliation: Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC 20007, USA.
authors.forename: Mónica L
authors.initials: ML
authors.lastname: Fiszman
authors.forename: Andrea
authors.initials: A
authors.lastname: Barberis
authors.forename: Congyi
authors.initials: C
authors.lastname: Lu
authors.forename: Zhanyan
authors.initials: Z
authors.lastname: Fu
authors.forename: Ferenc
authors.initials: F
authors.lastname: Erdélyi
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
mesh_terms: D000818:Animals; D001369:Axons / Q000737:chemistry; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000166:cytology*; D003712:Dendrites / Q000737:chemistry; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017930:Genes, Reporter; D007395:Interneurons / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate
references.citation: J Neurosci. 1998 Apr 15;18(8):2822-33
references.pmid: 9525999
references.citation: Nat Neurosci. 2001 Aug;4(8):787-93
references.pmid: 11477424
references.citation: J Neurosci. 1994 Oct;14(10):6102-20
references.pmid: 7931566
references.citation: J Neurosci. 1987 Jul;7(7):2203-13
references.pmid: 2886565
references.citation: J Physiol. 1998 Jun 15;509 ( Pt 3):817-31
references.pmid: 9596802
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4293-8
references.pmid: 12634427
references.citation: J Neurophysiol. 2004 Sep;92(3):1718-27
references.pmid: 15102896
references.citation: Neuroscience. 2002;114(1):123-33
references.pmid: 12207960
references.citation: J Neurosci. 1995 Apr;15(4):2656-67
references.pmid: 7722620
references.citation: Neuron. 2003 Jun 5;38(5):773-84
references.pmid: 12797961
references.citation: J Neurocytol. 1993 Sep;22(9):689-95
references.pmid: 7903688
references.citation: Cell. 1998 Mar 20;92(6):759-72
references.pmid: 9529252
references.citation: J Neurosci. 2004 Jun 23;24(25):5659-69
references.pmid: 15215288
references.citation: J Neurosci. 2002 Jun 1;22(11):4428-36
references.pmid: 12040050
references.citation: Neuron. 2004 Jan 8;41(1):113-26
references.pmid: 14715139
references.citation: Annu Rev Cell Biol. 1990;6:433-60
references.pmid: 1980418
references.citation: J Neurosci. 2003 Nov 19;23(33):10475-86
references.pmid: 14627631
references.citation: J Neurosci Res. 2003 May 1;72(3):317-26
references.pmid: 12692898
references.citation: J Neurosci. 1999 May 1;19(9):3277-86
references.pmid: 10212287
references.citation: Neuroreport. 1995 Jun 19;6(9):1285-9
references.pmid: 7669988
references.citation: J Neurosci. 2000 Jul 15;20(14):5217-24
references.pmid: 10884305
references.citation: J Neurosci. 2004 Nov 3;24(44):9770-8
references.pmid: 15525762
references.citation: Neurosci Lett. 1989 Jul 3;101(3):241-6
references.pmid: 2549463
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):7158-63
references.pmid: 15103023
references.citation: J Neurosci. 1997 Dec 1;17(23):9104-12
references.pmid: 9364057
references.citation: Brain Res. 1996 Apr 1;714(1-2):49-56
references.pmid: 8861608
references.citation: Curr Opin Neurobiol. 2001 Jun;11(3):327-35
references.pmid: 11399431
references.citation: J Neurosci. 1998 Feb 1;18(3):948-55
references.pmid: 9437016
references.citation: Neuron. 2003 Dec 4;40(5):945-57
references.pmid: 14659093
references.citation: Cereb Cortex. 2004 Oct;14(10):1122-33
references.pmid: 15115742
references.citation: J Biol Chem. 1998 Nov 6;273(45):29394-9
references.pmid: 9792641
references.citation: Neurosci Lett. 1989 Aug 14;103(1):56-63
references.pmid: 2476693
references.citation: J Neurochem. 1996 Jan;66(1):369-77
references.pmid: 8522977
references.citation: Neuron. 2004 Mar 25;41(6):943-53
references.pmid: 15046726
references.citation: J Neurochem. 2002 Mar;80(6):1062-70
references.pmid: 11953456
references.citation: Nat Neurosci. 2004 May;7(5):525-33
references.pmid: 15097992
references.citation: J Neurosci. 2001 May 1;21(9):3009-16
references.pmid: 11312285
references.citation: J Neurosci. 1999 Jan 15;19(2):511-9
references.pmid: 9880571
references.citation: Nat Neurosci. 1999 Jan;2(1):24-30
references.pmid: 10195176