title: Computational analysis of the impact of chronic stress on intrinsic and synaptic excitability in the hippocampus.
abstract: Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.
authors.affiliation: National Center for Biological Sciences, Bangalore 560065, India.
authors.forename: Rishikesh
authors.initials: R
authors.lastname: Narayanan
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chattarji
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000465:Algorithms; D000818:Animals; D001284:Atrophy; D001703:Biophysics; D056654:CA3 Region, Hippocampal / Q000166:cytology*; D003198:Computer Simulation; D003712:Dendrites / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
references.citation: Cell Mol Neurobiol. 1981 Dec;1(4):325-34
references.pmid: 6765736
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Trends Neurosci. 1998 Dec;21(12):505-9
references.pmid: 9881846
references.citation: Hippocampus. 2002;12(2):245-57
references.pmid: 12000121
references.citation: Nat Neurosci. 2000 Sep;3(9):895-903
references.pmid: 10966620
references.citation: Science. 2008 Feb 29;319(5867):1260-4
references.pmid: 18218862
references.citation: Network. 2002 Aug;13(3):311-25
references.pmid: 12222816
references.citation: Physiol Rev. 2008 Apr;88(2):769-840
references.pmid: 18391179
references.citation: Brain Res. 1978 Dec 29;159(2):385-90
references.pmid: 728808
references.citation: J Neurosci. 2002 Aug 1;22(15):6810-8
references.pmid: 12151561
references.citation: Nature. 1998 Dec 3;396(6710):433-9
references.pmid: 9853749
references.citation: Neuroscience. 2004;125(3):759-67
references.pmid: 15099689
references.citation: Proc Natl Acad Sci U S A. 1996 May 14;93(10):4750-3
references.pmid: 8643474
references.citation: Curr Biol. 2001 Jan 9;11(1):R10-2
references.pmid: 11166188
references.citation: Philos Trans R Soc Lond B Biol Sci. 2003 Apr 29;358(1432):667-74
references.pmid: 12740112
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12320-2
references.pmid: 11675480
references.citation: Nature. 2005 Mar 10;434(7030):221-5
references.pmid: 15759002
references.citation: Nature. 1996 Jul 25;382(6589):363-6
references.pmid: 8684467
references.citation: Nat Rev Neurosci. 2002 Jun;3(6):453-62
references.pmid: 12042880
references.citation: Neural Comput. 2005 Jan;17(1):75-96
references.pmid: 15563748
references.citation: Neuron. 2001 Mar;29(3):779-96
references.pmid: 11301036
references.citation: J Physiol. 2001 Apr 15;532(Pt 2):285
references.pmid: 11306649
references.citation: Brain Res. 1992 Aug 21;588(2):341-5
references.pmid: 1393587
references.citation: Nat Rev Neurosci. 2003 Nov;4(11):885-900
references.pmid: 14595400
references.citation: J Neurosci. 1982 Jan;2(1):32-48
references.pmid: 7054394
references.citation: Nat Neurosci. 2002 Nov;5(11):1111-3
references.pmid: 12404003
references.citation: Physiol Rev. 2008 Oct;88(4):1407-47
references.pmid: 18923186
references.citation: J Neurosci. 1990 Sep;10(9):3178-82
references.pmid: 1697902
references.citation: Cell. 2001 Nov 30;107(5):617-29
references.pmid: 11733061
references.citation: Brain Res. 2002 Jun 21;941(1-2):11-28
references.pmid: 12031543
references.citation: Neuroscience. 1995 Nov;69(1):89-98
references.pmid: 8637636
references.citation: Nat Rev Neurosci. 2008 May;9(5):357-69
references.pmid: 18425090
references.citation: Hippocampus. 2004;14(3):281-91
references.pmid: 15132427
references.citation: Nat Neurosci. 2004 Feb;7(2):126-35
references.pmid: 14730307
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4363-7
references.pmid: 1350090
references.citation: Nat Rev Neurosci. 2008 May;9(5):387
references.pmid: 18401345
references.citation: Neuroendocrinology. 1998 Jan;67(1):58-66
references.pmid: 9485170
references.citation: Neuroscience. 1995 Nov;69(1):83-8
references.pmid: 8637635
references.citation: Nat Rev Neurosci. 2008 Jan;9(1):65-75
references.pmid: 18094707
references.citation: Neuron. 2007 Nov 21;56(4):582-92
references.pmid: 18031678
references.citation: J Comput Neurosci. 1999 Jul-Aug;7(1):5-15
references.pmid: 10481998
references.citation: Science. 2002 Jul 12;297(5579):211-8
references.pmid: 12040087
references.citation: Annu Rev Neurosci. 1995;18:319-57
references.pmid: 7605065
references.citation: J Neurobiol. 2005 Jul;64(1):100-15
references.pmid: 15884001
references.citation: Neuron. 2001 Jan;29(1):157-69
references.pmid: 11182088
references.citation: Trends Neurosci. 1996 Apr;19(4):126-30
references.pmid: 8658594
references.citation: Trends Neurosci. 2008 Jun;31(6):309-16
references.pmid: 18471907
references.citation: J Physiol. 1998 Feb 15;507 ( Pt 1):237-47
references.pmid: 9490845
references.citation: J Neurosci. 1996 May 15;16(10):3534-40
references.pmid: 8627386
references.citation: Trends Neurosci. 1993 Dec;16(12):521-7
references.pmid: 7509523
references.citation: Eur J Neurosci. 2002 Sep;16(5):807-16
references.pmid: 12372016
references.citation: J Physiol. 2003 Apr 1;548(Pt 1):245-58
references.pmid: 12598591
references.citation: J Neurophysiol. 2001 Feb;85(2):926-37
references.pmid: 11160523
references.citation: Neuron. 2000 Mar;25(3):707-15
references.pmid: 10774737
references.citation: J Neurophysiol. 1995 Mar;73(3):1157-68
references.pmid: 7608762
references.citation: Annu Rev Neurosci. 1999;22:105-22
references.pmid: 10202533
references.citation: Epilepsia. 1996 Sep;37(9):879-91
references.pmid: 8814102
references.citation: Neural Comput. 1997 Aug 15;9(6):1179-209
references.pmid: 9248061
references.citation: J Neurosci Methods. 1998 Oct 1;84(1-2):49-54
references.pmid: 9821633
references.citation: J Physiol. 1995 Aug 15;487(1):67-90
references.pmid: 7473260
references.citation: Neural Comput. 2000 May;12(5):995-1007
references.pmid: 10905805
references.citation: J Physiol. 1983 Jan;334:33-46
references.pmid: 6306230
references.citation: Neuroscience. 2004;125(2):337-47
references.pmid: 15062977