title: Interictal spikes in developing rats cause long-standing cognitive deficits.
abstract: Frequent interictal spikes are a common finding in the electroencephalograms of children with epileptic encephalopathies. While it is well recognized that interictal spikes are a biological marker of seizures and can lead to transitory cognitive impairment, whether interictal spikes can result in long-standing adverse effects on learning and memory in children is not known. Here we investigated the consequences of interictal spikes in rat pups without seizures on long-term learning and memory. Rat pups were given a low dose of flurothyl for 4h for 10 days during continuous electroencephalographic monitoring. Rats developed interictal spikes without seizures while age-matched controls under similar testing conditions had few interictal spikes. When rats were tested as adults, there was impairment in reference memory in the probe test of the Morris water maze, reference memory impairment in the four-trial radial-arm water maze and impaired long-term potentiation. Early-life interictal spikes resulted in impaired new cell formation and decreased cell counts in the hippocampus but did not cause an increase in apoptosis. This study, for the first time demonstrates that interictal spikes in rat pups without seizures can result in long-standing spatial cognitive impairment. Our findings suggest that suppressing IIS may be as important as treating seizures during brain development.
authors.affiliation: Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Hanover, New Hampshire 03756, USA.
authors.forename: Omar I
authors.initials: OI
authors.lastname: Khan
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Forrest
authors.initials: F
authors.lastname: Miller
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Holmes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003292:Convulsants / Q000494:pharmacology; D004567:Electrodes, Implanted; D004569:Electroencephalography; D005481:Flurothyl / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D003292:Convulsants; D005481:Flurothyl
references.citation: Biomed Pharmacother. 1998;52(6):252-8
references.pmid: 9755824
references.citation: J Biol Chem. 1995 Feb 17;270(7):3255-60
references.pmid: 7531702
references.citation: Nature. 1982 Jun 24;297(5868):681-3
references.pmid: 7088155
references.citation: Epilepsy Res. 2009 Aug;85(2-3):305-10
references.pmid: 19464149
references.citation: Ann Neurol. 1998 Dec;44(6):845-57
references.pmid: 9851428
references.citation: Exp Neurol. 2003 Nov;184(1):196-213
references.pmid: 14637092
references.citation: J Clin Exp Neuropsychol. 1989 Oct;11(5):675-91
references.pmid: 2808657
references.citation: Perspect Dev Neurobiol. 1995;2(4):399-407
references.pmid: 7757409
references.citation: Curr Opin Pharmacol. 2008 Feb;8(1):75-81
references.pmid: 17827063
references.citation: Epilepsia. 2004 Dec;45(12):1539-48
references.pmid: 15571512
references.citation: Ann Neurol. 2007 May;61(5):411-26
references.pmid: 17323345
references.citation: Epilepsy Res. 2009 Dec;87(2-3):286-9
references.pmid: 19828295
references.citation: Eur J Neurosci. 2006 Mar;23(6):1559-66
references.pmid: 16553619
references.citation: Brain Res. 1984 Jul;317(1):113-23
references.pmid: 6467026
references.citation: J Clin Neurophysiol. 1984 Apr;1(2):109-42
references.pmid: 6443570
references.citation: Epilepsia. 2009 Aug;50 Suppl 7:37-42
references.pmid: 19682049
references.citation: Epilepsia. 2008 Jun;49 Suppl 5:50-4
references.pmid: 18522600
references.citation: Epilepsy Res. 2008 Nov;82(1):15-20
references.pmid: 18674885
references.citation: Nature. 2006 Dec 7;444(7120):707-12
references.pmid: 17151658
references.citation: Neurology. 1997 Oct;49(4):975-80
references.pmid: 9339676
references.citation: Nat Rev Neurol. 2009 Jul;5(7):380-91
references.pmid: 19578345
references.citation: J Neurosci Methods. 1984 May;11(1):47-60
references.pmid: 6471907
references.citation: Physiol Rev. 2005 Jul;85(3):883-941
references.pmid: 15987798
references.citation: Brain Res Dev Brain Res. 1999 Dec 10;118(1-2):99-107
references.pmid: 10611508
references.citation: Epilepsy Behav. 2005 Dec;7(4):629-38
references.pmid: 16246633
references.citation: Exp Neurol. 2009 Jan;215(1):167-77
references.pmid: 19000675
references.citation: Neurology. 1968 Mar;18(3):282-3
references.pmid: 5690349
references.citation: Ann N Y Acad Sci. 2007 Dec;1122:69-82
references.pmid: 18077565
references.citation: Epilepsy Behav. 2006 May;8(3):504-15
references.pmid: 16540376
references.citation: Neurobiol Learn Mem. 2001 Jul;76(1):81-105
references.pmid: 11525255
references.citation: Neuropsychologia. 1977;15(2):257-67
references.pmid: 846634
references.citation: J Histochem Cytochem. 1996 Sep;44(9):959-68
references.pmid: 8773561
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1997 Jan;21(1):47-68
references.pmid: 9075258
references.citation: Brain. 2001 Dec;124(Pt 12):2476-89
references.pmid: 11701601
references.citation: Epilepsy Res. 2009 Aug;85(2-3):221-30
references.pmid: 19395239
references.citation: J Neurosci. 2008 Aug 6;28(32):7979-90
references.pmid: 18685023
references.citation: Pediatr Res. 2009 Oct;66(4):435-40
references.pmid: 20016413
references.citation: J Pharmacol Sci. 2006;100(5):433-42
references.pmid: 16799259
references.citation: Fiziol Zh (1994). 2009;55(1):57-60
references.pmid: 19441716
references.citation: Brain Res. 1984 Jul;317(1):125-8
references.pmid: 6467027
references.citation: Adv Neurol. 1986;44:275-99
references.pmid: 3518347
references.citation: Eur J Neurosci. 2009 Mar;29(6):1153-64
references.pmid: 19302151
references.citation: Fiziol Zh (1994). 2008;54(5):40-5
references.pmid: 19058511
references.citation: Epilepsy Behav. 2004 Feb;5 Suppl 1:S3-13
references.pmid: 14725841
references.citation: Curr Opin Neurol. 2001 Apr;14(2):193-7
references.pmid: 11262735
references.citation: Expert Opin Pharmacother. 2003 Nov;4(11):2039-48
references.pmid: 14596657
references.citation: Electroencephalogr Clin Neurophysiol. 1988 Apr;69(4):338-52
references.pmid: 2450732
references.citation: Brain Res. 1981 Mar 23;209(1):61-76
references.pmid: 7214164
references.citation: J Clin Neurophysiol. 2003 Nov-Dec;20(6):393-7
references.pmid: 14734929
references.citation: Biochem Soc Trans. 2007 Apr;35(Pt 2):421-3
references.pmid: 17371290
references.citation: Epilepsia. 2000;41 Suppl 2:S2-6
references.pmid: 10885734
references.citation: Exp Neurol. 2009 Jun;217(2):378-87
references.pmid: 19345685
references.citation: Ann Neurol. 1988 Feb;23(2):131-7
references.pmid: 3377436
references.citation: Hippocampus. 2001;11(6):715-25
references.pmid: 11811666
references.citation: J Neurosci Res. 1999 Oct 1;58(1):62-75
references.pmid: 10491572
references.citation: Epilepsia. 2001;42 Suppl 6:9-12
references.pmid: 11902323
references.citation: Methods Mol Biol. 2007;399:1-14
references.pmid: 18309921
references.citation: Neuropharmacology. 2007 Dec;53(8):942-50
references.pmid: 17959201
references.citation: Electroencephalogr Clin Neurophysiol. 1988 Apr;69(4):319-37
references.pmid: 2450731
references.citation: Brain Res. 1981 Apr;227(2):269-81
references.pmid: 6261890
references.citation: Curr Mol Med. 2002 Nov;2(7):605-11
references.pmid: 12420800
references.citation: Brain Res. 1998 Mar 2;785(2):236-44
references.pmid: 9518631
references.citation: Dev Med Child Neurol. 1997 Jul;39(7):430-40
references.pmid: 9285433
references.citation: Exp Neurol. 1964 Apr;9:286-304
references.pmid: 14145629
references.citation: Brain. 1984 Mar;107 ( Pt 1):293-308
references.pmid: 6421454
references.citation: J Neurosci. 2001 Mar 15;21(6):2094-103
references.pmid: 11245693
references.citation: J Neurosci. 2008 May 7;28(19):5053-62
references.pmid: 18463258