alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents.
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.
Carr
David B
DB
Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Suite 403 BSB, Charleston, SC 29425, USA.
Andrews
Glenn D
GD
Glen
William B
WB
Lavin
A
A
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
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
J Biol Chem. 2005 Oct 7;280(40):34224-32
16079136
J Neurosci. 1996 Aug 1;16(15):4596-603
8764648
Behav Neural Biol. 1994 Sep;62(2):134-9
7993303
J Cardiovasc Pharmacol. 1994;24 Suppl 1:S1-8
7533221
Annu Rev Neurosci. 2005;28:403-50
16022602
Annu Rev Physiol. 1996;58:299-327
8815797
J Neurophysiol. 2001 Feb;85(2):855-68
11160518
Nature. 1989 Aug 31;340(6236):715-8
2475782
J Physiol. 1987 Feb;383:487-98
2888877
J Neurosci. 2006 Mar 22;26(12):3229-44
16554474
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5123-8
15051886
Neuron. 2006 Dec 21;52(6):1027-36
17178405
J Neurophysiol. 1990 Jun;63(6):1385-400
2358882
J Neurosci. 2005 Sep 21;25(38):8776-87
16177047
J Neurosci. 2006 Jul 26;26(30):7995-8003
16870744
Cell. 2004 Nov 24;119(5):719-32
15550252
Psychopharmacology (Berl). 1997 May;131(2):196-206
9201809
Nat Neurosci. 1999 Sep;2(9):848
10461231
Trends Neurosci. 2004 Jan;27(1):48-53
14698610
J Neurosci. 2000 Mar 15;20(6):RC65
10704519
J Physiol. 1997 Aug 15;503 ( Pt 1):87-97
9288677
Biochemistry. 1997 May 27;36(21):6415-23
9174358
Brain Res. 2001 May 25;902(1):108-18
11376600
J Neurophysiol. 2007 May;97(5):3432-8
17376848
Cereb Cortex. 1998 Apr-May;8(3):269-77
9617922
J Neurosci. 1998 Oct 1;18(19):7613-24
9742133
Neuron. 1989 Jun;2(6):1535-40
2483327
J Gen Physiol. 2001 May;117(5):491-504
11331358
Mol Pharmacol. 1996 Aug;50(2):407-14
8700150
Brain Res. 1997 Sep 19;769(1):108-18
9374278
Cell. 2007 Apr 20;129(2):397-410
17448997
J Neurosci. 2005 Oct 5;25(40):9162-70
16207875
J Physiol. 1993 Mar;462:753-64
8392580
Annu Rev Physiol. 2003;65:453-80
12471170
Neuropsychopharmacology. 2006 Mar;31(3):594-601
15999146
J Neurosci. 2004 Nov 17;24(46):10289-301
15548642
J Pharmacol Exp Ther. 1994 Sep;270(3):946-57
7932207
J Neurosci. 2000 Dec 15;20(24):8987-95
11124974
Brain Res Mol Brain Res. 1994 Jan;21(1-2):133-49
8164514
Trends Pharmacol Sci. 1998 Mar;19(3):87-93
9584624
Neuropsychopharmacology. 1999 Nov;21(5):611-21
10516957
Nat Neurosci. 2000 Nov;3 Suppl:1184-91
11127836
J Neurosci Res. 2003 Feb 15;71(4):516-25
12548707
J Physiol. 1992 Feb;447:729-53
1593463
J Neurochem. 2000 Jan;74(1):263-9
10617128
Neuropsychopharmacology. 1999 Nov;21(5):601-10
10516956
J Neurophysiol. 1998 Oct;80(4):2200-5
9772271
Neuropharmacology. 2003 Dec;45(8):1070-9
14614950
Rev Physiol Biochem Pharmacol. 2002;145:47-179
12224528
J Neurophysiol. 1998 Sep;80(3):1094-104
9744924
Neurochem Int. 2006 Dec;49(7):698-707
16962210
J Neurosci. 2002 Oct 1;22(19):8771-7
12351753
J Neurosci Methods. 2004 Dec 30;140(1-2):163-8
15589346
Eur J Neurosci. 1999 Feb;11(2):599-603
10051760