A novel role for {gamma}-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons.
With a multitude of substrates, γ-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of γ-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of γ-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support γ-secretase activity. Treatment of WT neuronal cultures with γ-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for γ-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Kara G
KG
Pratt
Ping
P
Zhu
Hirofumi
H
Watari
David G
DG
Cook
Jane M
JM
Sullivan
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D005071:Evoked Potentials / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D053764:Presenilin-1 / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
D015220:Calcium Channels; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; D053829:Amyloid Precursor Protein Secretases
J Neurophysiol. 2005 Dec;94(6):4421-9
16148264
Cell. 2006 May 19;125(4):785-99
16713568
Science. 2000 Aug 11;289(5481):953-7
10937999
J Neurophysiol. 2009 May;101(5):2290-6
19261712
Neuron. 2001 Sep 13;31(5):713-26
11567612
Neuron. 2003 Mar 27;37(6):925-37
12670422
Neuron. 2003 Jul 17;39(2):299-308
12873386
Nature. 2009 Jul 30;460(7255):632-6
19641596
Hum Gene Ther. 2001 Jun 10;12(9):1103-8
11399231
J Neurosci. 2009 Jul 29;29(30):9458-70
19641109
Nature. 1999 Apr 8;398(6727):513-7
10206644
Nature. 2000 Aug 24;406(6798):889-93
10972290
Neuron. 2003 Jun 19;38(6):929-39
12818178
Neuron. 2001 Jan;29(1):197-208
11182091
Nat Neurosci. 1999 Jan;2(1):44-9
10195179
Int J Biochem Cell Biol. 2008;40(1):84-97
17709274
CNS Neurosci Ther. 2010 Oct;16(5):272-84
20560993
J Physiol. 1987 Dec;394:149-72
2451016
Nature. 1998 Jan 22;391(6665):387-90
9450754
J Neurosci. 2002 Jan 1;22(1):21-8
11756484
Nature. 2005 May 26;435(7041):497-501
15917809
Neurosci Lett. 2002 Feb 8;319(1):37-40
11814648
Neuron. 2000 Sep;27(3):561-72
11055438
Annu Rev Physiol. 2002;64:355-405
11826273
Neuron. 2008 Jun 26;58(6):871-83
18579078
Neuroscientist. 2008 Dec;14(6):609-25
19029059
J Neurosci. 2005 Feb 9;25(6):1540-9
15703408
J Biol Chem. 2003 Nov 7;278(45):44393-9
12902342
Cell. 2006 Sep 8;126(5):981-93
16959576
Neuron. 2001 Dec 6;32(5):911-26
11738035
Neuron. 2001 Oct 25;32(2):181-4
11683989
Nat Rev Neurosci. 2002 Nov;3(11):862-72
12415294
Neuroscientist. 2005 Apr;11(2):110-5
15746379
Cell. 1997 May 16;89(4):629-39
9160754
Trends Neurosci. 2008 Sep;31(9):454-63
18675468
Neuroscience. 2004;124(3):501-5
14980721
Neurobiol Aging. 2008 May;29(5):639-52
17222948
Neuron. 2003 Apr 10;38(1):9-12
12691659
Neuron. 1996 Jul;17(1):181-90
8755489