Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis.
The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of phospholipase Cgamma1 (PLCgamma1) signaling is the key pathway and tested this in trkB(PLC/PLC) mice carrying a mutation (Y816F) that uncouples TrkB from PLCgamma1. Biochemical measures revealed activation of both TrkB and PLCgamma1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLCgamma1 activation was decreased in hippocampi isolated from trkB(PLC/PLC) compared with control mice. Epileptogenesis assessed by development of kindling was inhibited in trkB(PLC/PLC) compared with control mice. Long-term potentiation of the mossy fiber-CA3 pyramid synapse was impaired in slices of trkB(PLC/PLC) mice. We conclude that TrkB-dependent activation of PLCgamma1 signaling is an important molecular mechanism of limbic epileptogenesis. Elucidating signaling pathways activated by a cell membrane receptor in animal models of CNS disorders promises to reveal novel targets for specific and effective therapeutic intervention.
He
Xiao Ping
XP
Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710, USA.
Pan
Enhui
E
Sciarretta
Carla
C
Minichiello
Liliana
L
McNamara
James O
JO
D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D007696:Kindling, Neurologic / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051966:Phospholipase C gamma / Q000096:biosynthesis / Q000502:physiology*; D010862:Pilocarpine; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000378:metabolism
D010862:Pilocarpine; D020813:Receptor, trkB; D051966:Phospholipase C gamma
Neuron. 2009 Mar 26;61(6):820-38
19323993
Nat Rev Neurosci. 2009 Dec;10(12):850-60
19927149
Epilepsy Res. 2002 Sep;51(1-2):93-107
12350385
J Comp Neurol. 2000 Mar 20;418(4):411-22
10713570
J Neurosci. 2002 Dec 1;22(23):10399-407
12451139
Brain Res Mol Brain Res. 1994 Apr;23(1-2):135-43
7913202
Brain Res. 1999 Feb 13;818(2):579-82
10082852
Nat Rev Neurosci. 2005 Jun;6(6):449-62
15891778
J Neurosci. 2004 Dec 15;24(50):11346-55
15601941
J Neurosci. 2000 Nov 15;20(22):8279-89
11069934
Neuroscience. 1997 May;78(2):431-48
9145800
Neuron. 1998 Aug;21(2):335-45
9728915
J Neurosci. 2007 Sep 12;27(37):9866-73
17855601
Neuron. 2002 Sep 26;36(1):121-37
12367511
Neuron. 1991 Jun;6(6):937-48
2054188
Eur J Neurosci. 1995 Jul 1;7(7):1527-35
7551179
Neuroscience. 2004;126(3):521-31
15183502
Sci STKE. 2006 Oct 10;2006(356):re12
17033045
Hippocampus. 2004;14(3):345-55
15132434
J Neurosci. 2007 Dec 19;27(51):14012-22
18094240
Neuron. 2009 Jul 16;63(1):27-39
19607790
J Neurosci. 1993 Feb;13(2):744-51
8381172
Exp Neurol. 2003 Jul;182(1):21-34
12821374
Science. 2002 Nov 15;298(5597):1418-21
12434059
Exp Brain Res. 1995;102(3):423-8
7737389
Hippocampus. 2010 Jan;20(1):113-24
19294647
Exp Neurol. 1995 Jun;133(2):215-24
7649227
J Physiol. 2005 Aug 1;566(Pt 3):747-58
15919713
J Neurosci. 2000 May 1;20(9):3434-41
10777806
Science. 1990 Jun 29;248(4963):1619-24
2114039
Brain Res. 1987 Sep 8;420(1):109-17
3676745
Neuroscience. 1999;93(4):1491-506
10501474
J Cell Biol. 2002 Dec 9;159(5):747-52
12473684
J Neurosci. 2004 May 12;24(19):4683-91
15140939
Neuron. 1996 Jun;16(6):1137-45
8663990
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8856-60
7568031
J Biol Chem. 2008 Jun 6;283(23):15799-806
18381284
J Neurosci. 2002 Sep 1;22(17):7502-8
12196573
Neuron. 2008 Feb 28;57(4):546-58
18304484
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
4110397
Nat Neurosci. 2008 Feb;11(2):131-3
18204444
Neuron. 2004 Jul 8;43(1):31-42
15233915
Neuron. 1991 Jul;7(1):165-76
1829904
Brain Res. 2008 Jul 24;1221:141-6
18550034
Hippocampus. 2002;12(2):258-68
12000122
J Neurosci. 1999 Jun 1;19(11):4616-26
10341259
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1716-21
9990090