title: Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function.
abstract: In many cortical neurons, HCN1 channels are the major contributors to Ih, the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of Ih in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of Ih decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or Ih blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question.
authors: Department of Neuroscience, Columbia University, New York, NY, USA.
authors: Sébastien J
authors: SJ
authors: Thuault
authors: Gaël
authors: G
authors: Malleret
authors: Christine M
authors: CM
authors: Constantinople
authors: Russell
authors: R
authors: Nicholls
authors: Irene
authors: I
authors: Chen
authors: Judy
authors: J
authors: Zhu
authors: Andrey
authors: A
authors: Panteleyev
authors: Svetlana
authors: S
authors: Vronskaya
authors: Matthew F
authors: MF
authors: Nolan
authors: Randy
authors: R
authors: Bruno
authors: Steven A
authors: SA
authors: Siegelbaum
authors: Eric R
authors: ER
authors: Kandel
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D056344:Executive Function / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology*; D012691:Serial Learning / Q000187:drug effects / Q000502:physiology; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D018377:Neurotransmitter Agents; D015221:Potassium Channels; D049452:Green Fluorescent Proteins
references: J Neurosci. 2003 Feb 15;23(4):1517-23
references: 12598640
references: Neuron. 2001 Dec 6;32(5):883-98
references: 11738033
references: Eur J Neurosci. 2004 Feb;19(3):643-9
references: 14984414
references: Cereb Cortex. 2002 Jan;12(1):1-16
references: 11734528
references: Brain Res. 1976 Mar 19;105(1):79-88
references: 1252960
references: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9538-43
references: 12093909
references: Neuron. 2009 Apr 30;62(2):171-89
references: 19409263
references: Behav Neurosci. 1985 Dec;99(6):1049-65
references: 3843539
references: J Neurosci. 2000 Jul 15;20(14):5264-75
references: 10884310
references: J Neurosci. 2010 Dec 15;30(50):16922-37
references: 21159963
references: Nat Neurosci. 1999 Jun;2(6):508-14
references: 10448214
references: Nat Neurosci. 2010 Jan;13(1):9-17
references: 19966841
references: PLoS One. 2007 Sep 12;2(9):e888
references: 17849017
references: J Neurosci. 1998 May 15;18(10):3501-10
references: 9570781
references: Nat Neurosci. 2003 Jan;6(1):51-8
references: 12483218
references: Neuron. 2001 May;30(2):319-33
references: 11394996
references: Nat Neurosci. 2003 Mar;6(3):316-22
references: 12592404
references: Nat Protoc. 2008;3(5):759-67
references: 18451784
references: PLoS Biol. 2004 Nov;2(11):e365
references: 15510225
references: Brain Res. 1981 Nov 23;225(1):51-65
references: 7296279
references: J Neurophysiol. 1993 Oct;70(4):1385-400
references: 8283204
references: Cereb Cortex. 2009 Mar;19(3):658-74
references: 18632738
references: Learn Mem. 2004 Jan-Feb;11(1):78-86
references: 14747520
references: Neuron. 2006 Mar 16;49(6):889-904
references: 16543136
references: Neuroscience. 2006 Apr 28;139(1):135-51
references: 16337341
references: J Virol. 1998 Nov;72(11):8463-71
references: 9765382
references: J Neurophysiol. 1998 Sep;80(3):1197-210
references: 9744932
references: Trends Neurosci. 2001 Aug;24(8):455-63
references: 11476885
references: J Neurosci. 1996 Jun 15;16(12):3848-61
references: 8656279
references: Brain Res. 1974 Apr 19;70(2):346-9
references: 4207718
references: J Neurosci. 2005 Sep 21;25(38):8776-87
references: 16177047
references: Cell. 2004 Nov 24;119(5):719-32
references: 15550252
references: J Neurosci. 1996 Aug 15;16(16):5154-67
references: 8756444
references: Psychon Bull Rev. 2002 Dec;9(4):637-71
references: 12613671
references: Nat Rev Neurosci. 2003 Oct;4(10):829-39
references: 14523382
references: Nat Neurosci. 2002 Nov;5(11):1185-93
references: 12389030
references: J Physiol. 1997 Jun 15;501 ( Pt 3):565-71
references: 9218217
references: Science. 2000 Jun 2;288(5471):1656-60
references: 10834847
references: J Neurosci. 2004 Nov 10;24(45):10117-27
references: 15537882
references: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18206-11
references: 15608064
references: Neuroscience. 2001;104(2):335-46
references: 11377838
references: Neurosci Lett. 2008 Jul 18;439(3):275-80
references: 18534748
references: Neuron. 2003 Sep 25;40(1):177-88
references: 14527442
references: J Neurosci. 2007 Nov 14;27(46):12440-51
references: 18003822
references: Physiol Rev. 1996 Jul;76(3):687-717
references: 8757786
references: J Neurosci. 1998 Oct 1;18(19):7613-24
references: 9742133
references: Nat Neurosci. 2009 Nov;12(11):1444-9
references: 19801988
references: J Neurosci. 2009 Jan 21;29(3):600-9
references: 19158287
references: Trends Neurosci. 1991 Feb;14(2):68-73
references: 1708539
references: J Physiol. 2005 Mar 1;563(Pt 2):583-96
references: 15618277
references: Biochem Biophys Res Commun. 2003 Nov 7;311(1):187-92
references: 14575712
references: Cell. 2003 Nov 26;115(5):551-64
references: 14651847
references: Nature. 1996 Aug 15;382(6592):629-32
references: 8757133
references: Cereb Cortex. 2003 Nov;13(11):1242-50
references: 14576215
references: Neurosci Biobehav Rev. 2001 May;25(3):275-86
references: 11378181
references: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4642-6
references: 17360577
references: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7514-9
references: 10377446
references: J Neurophysiol. 1988 Feb;59(2):450-67
references: 3351570
references: Science. 1971 Aug 13;173(3997):652-4
references: 4998337
references: Cereb Cortex. 1998 Jul-Aug;8(5):437-50
references: 9722087
references: J Neurophysiol. 1989 Feb;61(2):331-49
references: 2918358
references: Nature. 2002 Nov 14;420(6912):173-8
references: 12432392
references: Exp Neurol. 1984 Aug;85(2):283-96
references: 6086379
references: Brain Res. 1988 Dec 6;474(2):211-21
references: 3208130
references: Neuron. 1995 Mar;14(3):477-85
references: 7695894
references: Neuron. 2003 Nov 13;40(4):835-45
references: 14622586
references: Cell. 2007 Apr 20;129(2):397-410
references: 17448997
references: J Neurosci. 1992 Dec;12(12):4701-11
references: 1361197
references: Annu Rev Physiol. 2003;65:453-80
references: 12471170
references: Neuroscience. 2006 Apr 28;139(1):23-38
references: 16324795
references: Nature. 2011 Jul 27;476(7359):210-3
references: 21796118
references: Nature. 2003 May 15;423(6937):283-8
references: 12748641
references: J Neurosci. 1993 Aug;13(8):3252-65
references: 8340806
references: Behav Brain Res. 1997 Sep;87(2):115-25
references: 9331480
references: Behav Brain Res. 1986 Jun;20(3):295-301
references: 3741590
references: Exp Brain Res. 1995;104(2):337-48
references: 7672026
references: J Neurosci. 2009 Apr 15;29(15):4945-52
references: 19369563
references: Brain Res. 1991 May 10;548(1-2):81-93
references: 1678304
references: Neuron. 2003 Jan 23;37(2):361-7
references: 12546829
references: Nat Neurosci. 2000 Oct;3(10):1027-34
references: 11017176
references: Nat Neurosci. 2009 Feb;12(2):190-9
references: 19169252
references: J Physiol. 1996 Apr 1;492 ( Pt 1):97-106
references: 8730586
references: J Neurophysiol. 2000 May;83(5):3177-82
references: 10805715
references: J Neurosci. 1988 Nov;8(11):4007-26
references: 3183710
references: Nature. 1995 Nov 16;378(6554):279-81
references: 7477346
references: J Neurophysiol. 2009 Aug;102(2):735-51
references: 19458150
references: Neuron. 2006 Mar 2;49(5):735-46
references: 16504948
references: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7298-303
references: 18474856
references: J Neurosci. 2005 Jun 15;25(24):5803-14
references: 15958747
references: Neuroscience. 2006 Apr 28;139(1):181-93
references: 16337090
references: Hippocampus. 2007;17(4):257-63
references: 17315198
references: Psychopharmacology (Berl). 1995 May;119(2):139-44
references: 7659760
references: Annu Rev Psychol. 2008;59:193-224
references: 17854286