title: Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy.
abstract: Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.
authors.affiliation: Optical Approaches to Brain Function Laboratory Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Angela Michela
authors.initials: AM
authors.lastname: De Stasi
authors.affiliation: Optical Approaches to Brain Function Laboratory Fondazione EBRI "Rita Levi-Montalcini", Roma, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Farisello
authors.affiliation: CNR Neuroscience Institute and University of Padova, Padova, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Marcon
authors.affiliation: Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy Neural Computation Laboratory, Istituto Italiano di Tecnologia, Rovereto, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cavallari
authors.affiliation: Optical Approaches to Brain Function Laboratory Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Forli
authors.affiliation: Optical Approaches to Brain Function Laboratory Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Dania
authors.initials: D
authors.lastname: Vecchia
authors.affiliation: CNR Neuroscience Institute and University of Padova, Padova, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Losi
authors.affiliation: Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275 and University of Nice-Sophia Antipolis, Valbonne, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
authors.affiliation: Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy Neural Computation Laboratory, Istituto Italiano di Tecnologia, Rovereto, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Panzeri
authors.affiliation: CNR Neuroscience Institute and University of Padova, Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carmignoto
authors.affiliation: Fondazione EBRI "Rita Levi-Montalcini", Roma, Italy Sorbonne Universités UPMC Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, Paris, France ICM-Institut du Cerveau et de la Moelle épinière, Paris, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bacci
authors.affiliation: Optical Approaches to Brain Function Laboratory Neural Coding Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fellin
mesh_terms: D000200:Action Potentials; D000818:Animals; D058256:Brain Waves; D002540:Cerebral Cortex / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D007395:Interneurons / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D009434:Neural Pathways / Q000503:physiopathology; D053578:Opsoclonus-Myoclonus Syndrome / Q000235:genetics / Q000503:physiopathology*; D010320:Parvalbumins / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D055366:Synaptic Potentials
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D010320:Parvalbumins; C568249:Scn1a protein, mouse; D013004:Somatostatin
keywords: Dravet syndrome; Nav1.1; parvalbumin-positive interneurons; somatosensory cortex; somatostatin-positive interneurons
references.citation: Neuron. 2007 Oct 4;56(1):43-57
references.pmid: 17920014
references.citation: Nat Neurosci. 2013 Feb;16(2):227-34
references.pmid: 23313909
references.citation: Front Neuroanat. 2012 Jul 11;6:24
references.pmid: 22798946
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108 Suppl 3:15542-8
references.pmid: 21383190
references.citation: Nat Protoc. 2010 Feb;5(2):247-54
references.pmid: 20134425
references.citation: Epilepsia. 2010 Aug;51(8):1493-502
references.pmid: 20067512
references.citation: J Neurosci. 2014 Nov 5;34(45):14874-89
references.pmid: 25378155
references.citation: J Neurosci. 1993 Aug;13(8):3266-83
references.pmid: 8340807
references.citation: Epilepsia. 2014 Feb;55(2):245-55
references.pmid: 24417577
references.citation: Neurobiol Dis. 2015 May;77:35-48
references.pmid: 25725421
references.citation: Nat Rev Neurosci. 2012 Feb;13(2):107-20
references.pmid: 22251963
references.citation: PLoS Biol. 2010;8(4):e1000352
references.pmid: 20405049
references.citation: J Neurosci. 2013 Dec 11;33(50):19599-610
references.pmid: 24336724
references.citation: Brain. 2015 Aug;138(Pt 8):2219-33
references.pmid: 26017580
references.citation: Neuroscience. 2006;137(4):1087-106
references.pmid: 16343791
references.citation: Nat Neurosci. 2006 Sep;9(9):1142-9
references.pmid: 16921370
references.citation: Neuron. 2012 Oct 4;76(1):1-11
references.pmid: 23040802
references.citation: Nature. 2009 Jun 4;459(7247):663-7
references.pmid: 19396156
references.citation: Epilepsia. 2011 Nov;52(11):2050-6
references.pmid: 21801172
references.citation: J Neurosci. 2013 Jun 26;33(26):10750-61
references.pmid: 23804097
references.citation: J Neurosci. 1992 Dec;12(12):4701-11
references.pmid: 1361197
references.citation: Nat Rev Neurosci. 2008 Jul;9(7):557-68
references.pmid: 18568015
references.citation: Nat Rev Neurosci. 2013 Mar;14(3):202-16
references.pmid: 23385869
references.citation: Am J Hum Genet. 2001 Jun;68(6):1327-32
references.pmid: 11359211
references.citation: J Neurosci. 2004 Aug 4;24(31):6862-70
references.pmid: 15295020
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):97-107
references.pmid: 14735113
references.citation: J Clin Invest. 2005 Aug;115(8):2010-7
references.pmid: 16075041
references.citation: Science. 2014 Aug 1;345(6196):1255263
references.pmid: 25082707
references.citation: Dev Neurobiol. 2011 Jan 1;71(1):45-61
references.pmid: 21154909
references.citation: Nature. 2012 Sep 20;489(7416):385-90
references.pmid: 22914087
references.citation: Epilepsia. 2013 Jul;54(7):1251-61
references.pmid: 23663038
references.citation: Epilepsia. 2011 Nov;52(11):1949-55
references.pmid: 21910730
references.citation: Neuroscience. 2002;114(4):1115-32
references.pmid: 12379264
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13638-43
references.pmid: 14595013
references.citation: Neuron. 2013 Feb 6;77(3):388-405
references.pmid: 23395369
references.citation: Nat Neurosci. 2010 Jan;13(1):9-17
references.pmid: 19966841
references.citation: J Neurosci. 2010 Mar 10;30(10):3745-51
references.pmid: 20220008
references.citation: Neuron. 2011 Oct 20;72(2):231-43
references.pmid: 22017986
references.citation: J Neurosci. 2007 May 30;27(22):5903-14
references.pmid: 17537961
references.citation: Curr Opin Neurobiol. 2011 Dec;21(6):866-72
references.pmid: 21680173
references.citation: Nature. 2013 Nov 7;503(7474):51-8
references.pmid: 24201278
references.citation: Biochem Biophys Res Commun. 2002 Jul 5;295(1):17-23
references.pmid: 12083760
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):100-13
references.pmid: 20087360
references.citation: J Neurosci. 2003 Feb 15;23(4):1298-309
references.pmid: 12598618
references.citation: Adv Neurol. 2005;95:71-102
references.pmid: 15508915
references.citation: Nature. 2009 Jun 4;459(7247):698-702
references.pmid: 19396159
references.citation: Neuron. 2007 Oct 4;56(1):33-42
references.pmid: 17920013
references.citation: Neural Netw. 2004 Jun-Jul;17(5-6):633-46
references.pmid: 15288889
references.citation: J Neurosci. 2003 May 15;23(10):3963-71
references.pmid: 12764080
references.citation: J Neurosci. 2005 Jul 13;25(28):6490-8
references.pmid: 16014710
references.citation: Neuron. 2006 Jan 5;49(1):119-30
references.pmid: 16387644
references.citation: Nature. 2010 Apr 22;464(7292):1155-60
references.pmid: 20414303
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14646-51
references.pmid: 22908258
references.citation: J Neurosci. 2014 Jun 25;34(26):8875-93
references.pmid: 24966387
references.citation: Nat Med. 2006 Jul;12(7):817-23
references.pmid: 16819552
references.citation: Curr Opin Neurobiol. 2014 Jun;26:64-71
references.pmid: 24434607
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3139-48
references.pmid: 25024183
references.citation: Epilepsia. 2000;41 Suppl 9:7
references.pmid: 11156512
references.citation: Nat Neurosci. 2013 Nov;16(11):1671-7
references.pmid: 24097038
references.citation: J Physiol. 2013 Feb 15;591(4):807-22
references.pmid: 23207591
references.citation: J Neurosci. 1993 Aug;13(8):3284-99
references.pmid: 8340808
references.citation: J Neurosci. 1993 Aug;13(8):3252-65
references.pmid: 8340806