title: alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents.
abstract: Stimulation of alpha(2)-noradrenergic (NA) receptors within the PFC improves working memory performance. This improvement is accompanied by a selective increase in the activity of PFC neurons during delay periods, although the cellular mechanisms responsible for this enhanced response are largely unknown. Here we used current and voltage clamp recordings to characterize the response of layer V-VI PFC pyramidal neurons to alpha(2)-NA receptor stimulation. alpha(2)-NA receptor activation produced a small hyperpolarization of the resting membrane potential, which was accompanied by an increase in input resistance and evoked firing. Voltage clamp analysis demonstrated that alpha(2)-NA receptor stimulation inhibited a caesium and ZD7288-sensitive hyperpolarization-activated (HCN) inward current. Suppression of HCN current by alpha(2)-NA stimulation was not dependent on adenylate cyclase but instead required activation of a PLC-PKC linked signalling pathway. Similar to direct blockade of HCN channels, alpha(2)-NA receptor stimulation produced a significant enhancement in temporal summation during trains of distally evoked EPSPs. These dual effects of alpha(2)-NA receptor stimulation - membrane hyperpolarization and enhanced temporal integration - together produce an increase in the overall gain of the response of PFC pyramidal neurons to excitatory synaptic input. The net effect is the suppression of isolated excitatory inputs while enhancing the response to a coherent burst of synaptic activity.
authors: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Suite 403 BSB, Charleston, SC 29425, USA.
authors: David B
authors: DB
authors: Carr
authors: Glenn D
authors: GD
authors: Andrews
authors: William B
authors: WB
authors: Glen
authors: A
authors: A
authors: Lavin
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002586:Cesium / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D009473:Neuronal Plasticity; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011743:Pyrimidines; D018341:Receptors, Adrenergic, alpha-2; C082246:ICI D2788; D002586:Cesium; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D003000:Clonidine
references: J Biol Chem. 2005 Oct 7;280(40):34224-32
references: 16079136
references: J Neurosci. 1996 Aug 1;16(15):4596-603
references: 8764648
references: Behav Neural Biol. 1994 Sep;62(2):134-9
references: 7993303
references: J Cardiovasc Pharmacol. 1994;24 Suppl 1:S1-8
references: 7533221
references: Annu Rev Neurosci. 2005;28:403-50
references: 16022602
references: Annu Rev Physiol. 1996;58:299-327
references: 8815797
references: J Neurophysiol. 2001 Feb;85(2):855-68
references: 11160518
references: Nature. 1989 Aug 31;340(6236):715-8
references: 2475782
references: J Physiol. 1987 Feb;383:487-98
references: 2888877
references: J Neurosci. 2006 Mar 22;26(12):3229-44
references: 16554474
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5123-8
references: 15051886
references: Neuron. 2006 Dec 21;52(6):1027-36
references: 17178405
references: J Neurophysiol. 1990 Jun;63(6):1385-400
references: 2358882
references: J Neurosci. 2005 Sep 21;25(38):8776-87
references: 16177047
references: J Neurosci. 2006 Jul 26;26(30):7995-8003
references: 16870744
references: Cell. 2004 Nov 24;119(5):719-32
references: 15550252
references: Psychopharmacology (Berl). 1997 May;131(2):196-206
references: 9201809
references: Nat Neurosci. 1999 Sep;2(9):848
references: 10461231
references: Trends Neurosci. 2004 Jan;27(1):48-53
references: 14698610
references: J Neurosci. 2000 Mar 15;20(6):RC65
references: 10704519
references: J Physiol. 1997 Aug 15;503 ( Pt 1):87-97
references: 9288677
references: Biochemistry. 1997 May 27;36(21):6415-23
references: 9174358
references: Brain Res. 2001 May 25;902(1):108-18
references: 11376600
references: J Neurophysiol. 2007 May;97(5):3432-8
references: 17376848
references: Cereb Cortex. 1998 Apr-May;8(3):269-77
references: 9617922
references: J Neurosci. 1998 Oct 1;18(19):7613-24
references: 9742133
references: Neuron. 1989 Jun;2(6):1535-40
references: 2483327
references: J Gen Physiol. 2001 May;117(5):491-504
references: 11331358
references: Mol Pharmacol. 1996 Aug;50(2):407-14
references: 8700150
references: Brain Res. 1997 Sep 19;769(1):108-18
references: 9374278
references: Cell. 2007 Apr 20;129(2):397-410
references: 17448997
references: J Neurosci. 2005 Oct 5;25(40):9162-70
references: 16207875
references: J Physiol. 1993 Mar;462:753-64
references: 8392580
references: Annu Rev Physiol. 2003;65:453-80
references: 12471170
references: Neuropsychopharmacology. 2006 Mar;31(3):594-601
references: 15999146
references: J Neurosci. 2004 Nov 17;24(46):10289-301
references: 15548642
references: J Pharmacol Exp Ther. 1994 Sep;270(3):946-57
references: 7932207
references: J Neurosci. 2000 Dec 15;20(24):8987-95
references: 11124974
references: Brain Res Mol Brain Res. 1994 Jan;21(1-2):133-49
references: 8164514
references: Trends Pharmacol Sci. 1998 Mar;19(3):87-93
references: 9584624
references: Neuropsychopharmacology. 1999 Nov;21(5):611-21
references: 10516957
references: Nat Neurosci. 2000 Nov;3 Suppl:1184-91
references: 11127836
references: J Neurosci Res. 2003 Feb 15;71(4):516-25
references: 12548707
references: J Physiol. 1992 Feb;447:729-53
references: 1593463
references: J Neurochem. 2000 Jan;74(1):263-9
references: 10617128
references: Neuropsychopharmacology. 1999 Nov;21(5):601-10
references: 10516956
references: J Neurophysiol. 1998 Oct;80(4):2200-5
references: 9772271
references: Neuropharmacology. 2003 Dec;45(8):1070-9
references: 14614950
references: Rev Physiol Biochem Pharmacol. 2002;145:47-179
references: 12224528
references: J Neurophysiol. 1998 Sep;80(3):1094-104
references: 9744924
references: Neurochem Int. 2006 Dec;49(7):698-707
references: 16962210
references: J Neurosci. 2002 Oct 1;22(19):8771-7
references: 12351753
references: J Neurosci Methods. 2004 Dec 30;140(1-2):163-8
references: 15589346
references: Eur J Neurosci. 1999 Feb;11(2):599-603
references: 10051760