title: Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice.
abstract: Young, but not adult, fragile X mental retardation gene (Fmr1) knockout (KO) mice display audiogenic seizures (AGS) that can be prevented by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation. In order to identify the cerebral regions involved in these phenomena, we characterized the response to AGS in Fmr1 KO mice and wild type (WT) controls at postnatal day (P) 45 and P90. To characterize the diverse response to AGS in various cerebral regions, we evaluated the activity markers FosB/ΔFosB and phosphorylated ERK1/2 (p-ERK1/2). Wild running (100% of tested mice) followed by clonic/tonic seizures (30%) were observed in P45 Fmr1 KO mice, but not in WT mice. In P90 Fmr1 KO mice, wild running was only present in 25% of tested animals. Basal FosB/ΔFosB immunoreactivity was higher (P < 0.01 vs. WT) in the CA1 and subiculum of P45 Fmr1 KO mice. Following the AGS test, FosB/ΔFosB expression consistently increased in most of the analyzed regions in both groups at P45, but not at P90. Interestingly, FosB/ΔFosB immunoreactivity was significantly higher in P45 Fmr1 KO mice in the medial geniculate body (P < 0.05 vs. WT) and CA3 (P < 0.01). Neurons presenting with immunopositivity to p-ERK1/2 were more abundant in the subiculum of Fmr1 KO mice in control condition (P < 0.05 vs. WT, in both age groups). In this region, p-ERK1/2-immunopositive cells significantly decreased (-75%, P < 0.01) in P90 Fmr1 KO mice exposed to the AGS test, but no changes were found in P45 mice or in other brain regions. In both age groups of WT mice, p-ERK1/2-immunopositive cells increased in the subiculum after exposure to the acoustic test. Our findings illustrate that FosB/ΔFosB markers are overexpressed in the medial geniculate body and CA3 in Fmr1 KO mice experiencing AGS, and that p-ERK1/2 is markedly decreased in the subiculum of Fmr1 KO mice resistant to AGS induction. These findings suggest that resilience to AGS is associated with dephosphorylation of p-ERK1/2 in the subiculum of mature Fmr1 KO mice.
authors: Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia Modena, Italy.
authors: Giulia
authors: G
authors: Curia
authors: Fabio
authors: F
authors: Gualtieri
authors: Regina
authors: R
authors: Bartolomeo
authors: Riccardo
authors: R
authors: Vezzali
authors: Giuseppe
authors: G
authors: Biagini
keywords: FosB; Fragile X Syndrome; acoustic stimulus; epilepsy; extracellular signal-regulated kinase (ERK); geniculate body; hippocampus; subiculum
references: J Neurosci. 2010 Nov 17;30(46):15616-27
references: 21084617
references: EMBO J. 1995 Oct 16;14(20):5048-59
references: 7588633
references: Epilepsia. 2010 Dec;51(12):2470-3
references: 21204809
references: Hippocampus. 2006;16(10):843-60
references: 16897722
references: Curr Opin Neurobiol. 2006 Jun;16(3):265-9
references: 16707258
references: J Neurosci. 2007 Dec 19;27(51):13958-67
references: 18094233
references: J Child Neurol. 1999 Feb;14(2):108-12
references: 10073432
references: J Neurochem. 2004 May;89(3):654-9
references: 15086522
references: Brain. 2009 Oct;132(Pt 10):2805-21
references: 19755519
references: Am J Med Genet. 1991 Feb-Mar;38(2-3):511-3
references: 2018098
references: J Neurosci. 2008 Jul 30;28(31):7847-62
references: 18667617
references: Am J Med Genet A. 2008 Aug 1;146A(15):1911-6
references: 18627038
references: Neuron. 2012 Apr 12;74(1):49-56
references: 22500629
references: Psychoneuroendocrinology. 2006 Jul;31(6):781-5
references: 16621323
references: Epilepsia. 2000 Jan;41(1):19-23
references: 10643918
references: Am J Med Genet. 1999 Apr 2;83(4):268-79
references: 10208160
references: J Cell Biol. 2004 May 10;165(3):357-69
references: 15123736
references: Acta Neurochir Suppl. 2003;86:571-3
references: 14753508
references: Neurophysiol Clin. 1994 Dec;24(6):413-26
references: 7723725
references: J Pharmacol Exp Ther. 1973 Jan;184(1):1-10
references: 4686009
references: EMBO J. 2007 Nov 28;26(23):4891-901
references: 17972914
references: Epilepsy Curr. 2009 Jul-Aug;9(4):108-12
references: 19693328
references: Mol Cell Neurosci. 2002 Feb;19(2):138-51
references: 11860268
references: Brain Res. 2010 Apr 22;1326:143-51
references: 20188711
references: Epilepsia. 2011 Jan;52 Suppl 1:13-20
references: 21214535
references: J Neurosci. 1997 Jul 1;17(13):4933-41
references: 9185531
references: Front Behav Neurosci. 2009 Oct 05;3:24
references: 19838325
references: Science. 1967 Nov 17;158(3803):938-40
references: 6061899
references: Hippocampus. 2008;18(3):310-6
references: 18064708
references: Eur J Neurosci. 2010 Feb;31(4):599-612
references: 20384807
references: Ital J Neurol Sci. 1994 Oct;15(7):365-8
references: 7698895
references: Cell Mol Neurobiol. 2006 Feb;26(1):87-100
references: 16633904
references: Brain Res Brain Res Rev. 1998 Dec;28(3):370-490
references: 9858769
references: Exp Neurol. 2007 Jan;203(1):233-40
references: 17007840
references: Am J Intellect Dev Disabil. 2010 Nov;115(6):461-72
references: 20945999
references: Neurosci Lett. 1996 Apr 19;208(2):133-7
references: 8859908
references: Science. 2002 Nov 15;298(5597):1418-21
references: 12434059
references: Neuroscience. 2003;119(1):9-13
references: 12763063
references: J Neurobiol. 2006 Nov;66(13):1467-74
references: 17013930
references: Neuroscience. 1995 Nov;69(2):371-81
references: 8552235
references: Prog Neurobiol. 2002 Oct;68(3):167-207
references: 12450487
references: Seizure. 2001 Jan;10(1):60-3
references: 11181100
references: J Cell Biochem. 1998 Jun 15;69(4):392-413
references: 9620167
references: Int J Dev Neurosci. 1998 Jun-Jul;16(3-4):187-97
references: 9785115
references: Brain Res. 2009 Oct 13;1293:91-100
references: 19332034
references: Neuroscience. 2008 Sep 22;156(1):222-37
references: 18675888
references: Int J Neuropsychopharmacol. 2012 Aug;15(7):957-64
references: 21745437
references: Biol Psychiatry. 1993 May 15;33(10):712-9
references: 8353166
references: Cell. 1994 Jul 15;78(1):23-33
references: 8033209
references: Dev Med Child Neurol. 2002 Nov;44(11):724-8
references: 12418611
references: Epilepsia. 1999 Aug;40(8):1092-9
references: 10448821
references: J Neurochem. 2012 May;121(4):672-9
references: 22393900
references: Am J Hum Genet. 1995 Nov;57(5):1006-18
references: 7485149
references: Exp Mol Med. 2000 Dec 31;32(4):227-30
references: 11190275
references: Hum Mol Genet. 2002 Feb 15;11(4):371-8
references: 11854169
references: Neuropharmacology. 2005 Dec;49(7):1053-66
references: 16054174
references: Mol Cell Neurosci. 2010 Jan;43(1):43-50
references: 19837168
references: Epilepsy Res. 2003 Jun-Jul;55(1-2):21-7
references: 12948613
references: Brain Res Mol Brain Res. 2004 Nov 24;131(1-2):101-9
references: 15530658
references: Mol Psychiatry. 2009 Apr;14(4):448-61
references: 18227838
references: Nat Cell Biol. 2002 Aug;4(8):556-64
references: 12134156
references: Neuron. 2006 Aug 17;51(4):441-54
references: 16908410
references: Brain Dev. 2002 Dec;24(8):766-9
references: 12453600
references: Neuroscience. 2001;103(4):1043-50
references: 11301211
references: Cereb Cortex. 2009 Jul;19(7):1515-20
references: 18787232
references: Neuromolecular Med. 2005;7(4):325-42
references: 16391389
references: J Neurosci. 2011 Aug 17;31(33):11953-67
references: 21849556
references: J Neurosci. 2010 Aug 11;30(32):10624-38
references: 20702695
references: Epilepsia. 1988 Jan-Feb;29(1):41-7
references: 3338421
references: Curr Opin Neurol. 2000 Dec;13(6):715-20
references: 11148675
references: J Neuropathol Exp Neurol. 2008 Jul;67(7):687-701
references: 18596544