Long-term depression: A cell biological view

Philosophical Transactions of the Royal Society B: Biological Sciences

Volumn 369, Issue 1633, 2014, Pages

  Sheng, Morgan ^a   Ertürk, Ali ^a  

^a GENENTECH INC   (United States)

Author keywords

Caspase; Dendritic spine; Local apoptosis; Long term depression; Long term potentiation; Spine elimination

Indexed keywords

APOPTOSIS; BRAIN; CELL ORGANELLE; ENZYME ACTIVITY; MOLECULAR ANALYSIS; PHYSIOLOGICAL RESPONSE; SIGNALING;

AMPA RECEPTOR; CASPASE;

APOPTOSIS; DENDRITIC SPINE; HUMAN; LOCAL APOPTOSIS; LONG TERM DEPRESSION; LONG TERM POTENTIATION; METABOLISM; MITOCHONDRION; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION; SPINE ELIMINATION; SYNAPSE; SYNAPTIC TRANSMISSION;

CASPASE; DENDRITIC SPINE; LOCAL APOPTOSIS; LONG-TERM DEPRESSION; LONG-TERM POTENTIATION; SPINE ELIMINATION;

APOPTOSIS; CASPASES; HUMANS; LONG-TERM POTENTIATION; LONG-TERM SYNAPTIC DEPRESSION; MITOCHONDRIA; RECEPTORS, AMPA; SIGNAL TRANSDUCTION; SYNAPSES; SYNAPTIC TRANSMISSION;

EID: 84888778387     PISSN: 09628436     EISSN: 14712970     Source Type: Journal    
DOI: 10.1098/rstb.2013.0138     Document Type: Review

References (103)

1. Malenka RC, Bear MF. 2004 LTP and LTD: an embarrassment of riches. Neuron 44, 5-21. (doi:10.1016/j.neuron.2004.09.012)
2. Collingridge GL, Peineau S, Howland JG, Wang YT. 2010 Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459-473. (doi:10.1038/ nrn2867)
3. Bliss TV, Collingridge GL. 1993 A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31-39. (doi:10.1038/ 361031a0)
4. Kerchner GA, Nicoll RA. 2008 Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813-825. (doi:10. 1038/nrn2501)
5. Bear MF. 2003 Bidirectional synaptic plasticity: from theory to reality. Phil. Trans. R. Soc. Lond. B 358, 649-655. (doi:10.1098/rstb.2002.1255)
6. Thomas GM, Huganir RL. 2004 MAPK cascade signalling and synaptic plasticity. Nat. Rev. Neurosci. 5, 173-183. (doi:10.1038/nrn1346)
7. Shepherd JD, Huganir RL. 2007 The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613-643. (doi:10.1146/ annurev.cellbio.23.090506.123516)
8. Collingridge GL, Isaac JT, Wang YT. 2004 Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952-962. (doi:10.1038/nrn1556)
9. Malinow R, Malenka RC. 2002 AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103-126. (doi:10.1146/annurev. neuro.25.112701.142758)
10. Kerr JF, Wyllie AH, Currie AR. 1972 Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239-257. (doi:10.1038/bjc.1972.33)
11. Fuchs Y, Steller H. 2011 Programmed cell death in animal development and disease. Cell 147, 742-758. (doi:10.1016/j.cell.2011.10.033)
12. Kim WR, Sun W. 2011 Programmed cell death during postnatal development of the rodent nervous system. Dev. Growth Differ. 53, 225-235. (doi:10.1111/j.1440-169X.2010.01226.x)
13. Kuo CT, Zhu S, Younger S, Jan LY, Jan YN. 2006 Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron 51, 283-290. (doi:10.1016/j.neuron.2006.07.014)
14. Williams DW, Kondo S, Krzyzanowska A, Hiromi Y, Truman JW. 2006 Local caspase activity directs engulfment of dendrites during pruning. Nat. Neurosci. 9, 1234-1236. (doi:10.1038/nn1774)
15. Gilman CP, Mattson MP. 2002 Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility? Neuromolecular Med. 2, 197-214. (doi:10.1385/NMM:2:2:197)
16. Campbell DS, Holt CE. 2003 Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37, 939-952. (doi:10.1016/S0896-6273(03)00158-2)
17. Huesmann GR, Clayton DF. 2006 Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 52, 1061-1072. (doi:10.1016/j.neuron.2006.10.033)
18. Hyman BT, Yuan J. 2012 Apoptotic and nonapoptotic roles of caspases in neuronal physiology and pathophysiology. Nat. Rev. Neurosci. 13, 395-406. (doi:10.1038/nrn3228)
19. Tait SW, Green DR. 2010 Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621-632. (doi:10.1038/nrm2952)
20. Youle RJ, Strasser A. 2008 The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9, 47-59. (doi:10.1038/ nrm2308)
21. Srinivasula SM, Ashwell JD. 2008 IAPs: what's in a name? Mol. Cell 30, 123-135. (doi:10.1016/j. molcel.2008.03.008)
22. Riedl SJ, Shi Y. 2004 Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell Biol. 5, 897-907. (doi:10.1038/nrm1496)
23. Li Z et al. 2010 Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859-871. (doi:10.1016/j.cell.2010.03.053)
24. Jiao S, Li Z. 2011 Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70, 758-772. (doi:10.1016/j. neuron.2011.04.004)
25. Mattson MP, Keller JN, Begley JG. 1998 Evidence for synaptic apoptosis. Exp. Neurol. 153, 35-48. (doi:10.1006/exnr.1998.6863)
26. Lu C, Fu W, Salvesen GS, Mattson MP. 2002 Direct cleavage of AMPA receptor subunit GluR1 and suppression of AMPA currents by caspase-3: implications for synaptic plasticity and excitotoxic neuronal death. Neuromolecular Med. 1, 69-79. (doi:10.1385/NMM:1:1:69)
27. Rintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ. 2003 Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J. Neurosci. 23, 7881-7888.
28. Nishiyama M, Hong K, Mikoshiba K, Poo MM, Kato K. 2000 Calcium stores regulate the polarity and input specificity of synaptic modification. Nature 408, 584-588. (doi:10.1038/35046067)
29. Scanziani M, Nicoll RA, Malenka RC. 1996 Heterosynaptic long-term depression in the hippocampus. J. Physiol. Paris 90, 165-166. (doi:10.1016/S0928-4257(97)81416-7)
30. Christie BR, Stellwagen D, Abraham WC. 1995 Evidence for common expression mechanisms underlying heterosynaptic and associative long-term depression in the dentate gyrus. J. Neurophysiol. 74, 1244-1247.
31. Kemp N, McQueen J, Faulkes S, Bashir ZI. 2000 Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol. Eur. J. Neurosci. 12, 360-366. (doi:10.1046/ j.1460-9568.2000.00903.x)
32. Wagner JJ, Alger BE. 1995 GABAergic and developmental influences on homosynaptic LTD and depotentiation in rat hippocampus. J. Neurosci. 15, 1577-1586.
33. Oh WC, Hill TC, Zito K. 2013 Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening. Proc. Natl Acad. Sci. USA 110, E305-E312. (doi:10.1073/ pnas.1214705110)
34. Zhou Q, Homma KJ, Poo MM. 2004 Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749-757. (doi:10.1016/j.neuron.2004.11.011)
35. Crawford ED, Wells JA. 2011 Caspase substrates and cellular remodeling. Annu. Rev. Biochem. 80, 1055-1087. (doi:10.1146/annurev-biochem-061809-121639)
36. Hotulainen P, Hoogenraad CC. 2010 Actin in dendritic spines: connecting dynamics to function. J. Cell Biol. 189, 619-629. (doi:10.1083/jcb.201003008)
37. Salminen A, Suuronen T, Kaarniranta K. 2008 ROCK, PAK, and Toll of synapses in Alzheimer's disease. Biochem. Biophys. Res. Commun. 371, 587-590. (doi:10.1016/j.bbrc.2008.04.148)
38. Furukawa K, Fu W, Li Y, Witke W, Kwiatkowski DJ, Mattson MP. 1997 The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J. Neurosci. 17, 8178-8186.
39. Ursitti JA et al. 2001 Spectrins in developing rat hippocampal cells. Brain Res. Dev. Brain Res. 129, 81-93. (doi:10.1016/S0165-3806(01)00160-2)
40. Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J. 2001 Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat. Cell Biol. 3, 346-352. (doi:10.1038/35070019)
41. Kothakota S et al. 1997 Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278, 294-298. (doi:10.1126/science.278.5336.294)
42. Wang KK, Posmantur R, Nath R, McGinnis K, Whitton M, Talanian RV, Glantz SB, Morrow JS. 1998 Simultaneous degradation of alphaII-and betaII-spectrin by caspase 3 (CPP32) in apoptotic cells. J. Biol. Chem. 273, 22 490-22 497. (doi:10. 1074/jbc.273.35.22490)
43. Fasulo L, Ugolini G, Visintin M, Bradbury A, Brancolini C, Verzillo V, Novak M, Cattaneo A. 2000 The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J. Neurochem. 75, 624-633. (doi:10. 1046/j.1471-4159.2000.0750624.x)
44. Wang Y, Ju W, Liu L, Fam S, D'Souza S, Taghibiglou C, Salter M, Wang YT. 2004 α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor (AMPAR) endocytosis is essential for Nmethyl-D-aspartate-induced neuronal apoptosis. J. Biol. Chem. 279, 41 267-41 270. (doi:10.1074/ jbc.C400199200)
45. Halpain S, Hipolito A, Saffer L. 1998 Regulation of Factin stability in dendritic spines by glutamate receptors and calcineurin. J. Neurosci. 18, 9835-9844.
46. Winder DG, Sweatt JD. 2001 Roles of serine/ threonine phosphatases in hippocampal synaptic plasticity. Nat. Rev. Neurosci. 2, 461-474. (doi:10. 1038/35081514)
47. D'Amelio M et al. 2011 Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat. Neurosci. 14, 69-76. (doi:10.1038/nn.2709)
48. Mukerjee N, McGinnis KM, Park YH, Gnegy ME, Wang KK. 2000 Caspase-mediated proteolytic activation of calcineurin in thapsigargin-mediated apoptosis in SH-SY5Y neuroblastoma cells. Arch. Biochem. Biophys. 379, 337-343. (doi:10.1006/ abbi.2000.1889)
49. Peineau S et al. 2007 LTP inhibits LTD in the hippocampus via regulation of GSK3b. Neuron 53, 703-717. (doi:10.1016/j.neuron.2007.01.029)
50. Peineau S, Bradley C, Taghibiglou C, Doherty A, Bortolotto ZA, Wang YT, Collingride GL. 2008 The role of GSK-3 in synaptic plasticity. Br. J. Pharmacol. 153(Suppl. 1), S428-S437. (doi:10.1038/bjp.2008.2)
51. Asselin E, Mills GB, Tsang BK. 2001 XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res. 61, 1862-1868.
52. Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M. 2005 Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25, 11 300-11 312. (doi:10.1523/JNEUROSCI.2270-05.2005)
53. Sheng M, Kim E. 2011 The postsynaptic organization of synapses. Cold Spring Harbor Perspect. Biol. 3, a005678. (doi:10.1101/cshperspect. a005678)
54. Granger AJ, Shi Y, Lu W, Cerpas M, Nicoll RA. 2013 LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493, 495-500. (doi:10.1038/nature11775)
55. Sheng M, Malinow R, Huganir R. 2013 Neuroscience: strength in numbers. Nature 493, 482-483. (doi:10.1038/493482a)
56. Kim E, Sheng M. 2004 PDZ domain proteins of synapses. Nat. Rev. Neurosci. 5, 771-781. (doi:10.1038/nrn1517)
57. Sheng M, Hoogenraad CC. 2007 The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823-847. (doi:10.1146/annurev.biochem.76.060805.160029)
58. Kim MJ, Futai K, Jo J, Hayashi Y, Cho K, Sheng M. 2007 Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95. Neuron 56, 488-502. (doi:10.1016/j. neuron.2007.09.007)
59. Mulkey RM, Herron CE, Malenka RC. 1993 An essential role for protein phosphatases in hippocampal long-term depression. Science 261, 1051-1055. (doi:10.1126/science.8394601)
60. Nelson C et al. 2013 Phosphorylation of threonine-19 of PSD-95 by GSK-3b is required for PSD-95 mobilization and long-term depression. J. Neurosci. 33, 12 122-12 135. (doi:10.1523/JNEUROSCI.0131-13.2013)
61. Bingol B, Sheng M. 2011 Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69, 22-32. (doi:10. 1016/j.neuron.2010.11.006)
62. Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M. 2010 Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567-578. (doi:10.1016/j.cell.2010.01.024)
63. Fadok VA, Chimini G. 2001 The phagocytosis of apoptotic cells. Semin. Immunol. 13, 365-372. (doi:10.1006/smim.2001.0333)
64. Aguzzi A, Barres BA, Bennett ML. 2013 Microglia: scapegoat, saboteur, or something else? Science 339, 156-161. (doi:10.1126/science.1227901)
65. Stephan AH, Barres BA, Stevens B. 2012 The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369-339. (doi:10.1146/annurevneuro-061010-113810)
66. Schafer DP et al. 2012 Microglia sculpt postnatal neural circuits in an activity and complementdependent manner. Neuron 74, 691-705. (doi:10. 1016/j.neuron.2012.03.026)
67. Ricklin D, Hajishengallis G, Yang K, Lambris JD. 2010 Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785-797. (doi:10.1038/ni.1923)
68. Stevens B et al. 2007 The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164-1178. (doi:10.1016/j.cell.2007.10.036)
69. Paolicelli RC et al. 2011 Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458. (doi:10.1126/science.1202529)
70. Sheng ZH, Cai Q. 2012 Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat. Rev. Neurosci. 13, 77-93. (doi:10.1038/nrg3141)
71. Pivovarova NB, Pozzo-Miller LD, Hongpaisan J, Andrews SB. 2002 Correlated calcium uptake and release by mitochondria and endoplasmic reticulum of CA3 hippocampal dendrites after afferent synaptic stimulation. J. Neurosci. 22, 10 653-10 661.
72. Pacher P, Hajnoczky G. 2001 Propagation of the apoptotic signal by mitochondrial waves. Embo J. 20, 4107-4121. (doi:10.1093/emboj/20.15.4107)
73. 2+responses. Science 280, 1763-1766. (doi:10.1126/science.280. 5370.1763)
74. Csordas G, Thomas AP, Hajnoczky G. 1999 Quasisynaptic calcium signal transmission between endoplasmic reticulum and mitochondria. Embo J. 18, 96-108. (doi:10.1093/emboj/18.1.96)
75. 2+stores. J. Biol. Chem. 277, 9219-9225. (doi:10. 1074/jbc.M106817200)
76. 2+stores, is required for the induction of LTD in cultured cerebellar Purkinje cells. J. Neurophysiol. 74, 2184-2188.
77. 2+from separate presynaptic and postsynaptic intracellular stores. J. Neurosci. 16, 5951-5960.
78. Hamasaki M et al. 2013 Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389-393. (doi:10.1038/nature11910)
79. Selkoe DJ. 2002 Alzheimer's disease is a synaptic failure. Science 298, 789-791. (doi:10.1126/ science.1074069)
80. Luo L, O'Leary DD. 2005 Axon retraction and degeneration in development and disease. Annu. Rev. Neurosci. 28, 127-156. (doi:10.1146/annurev. neuro.28.061604.135632)
81. Urban L, Aitken PG, Friedman A, Somjen GG. 1990 An NMDA-mediated component of excitatory synaptic input to dentate granule cells in 'epileptic' human hippocampus studied in vitro. Brain Res. 515, 319-322. (doi:10.1016/0006-8993(90)90615-I)
82. Milnerwood AJ et al. 2010 Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 65, 178-190. (doi:10.1016/j.neuron.2010.01.008)
83. Sonkusare SK, Kaul CL, Ramarao P. 2005 Dementia of Alzheimer's disease and other neurodegenerative disorders-memantine, a new hope. Pharmacol. Res. 51, 1-17. (doi:10.1016/j.phrs.2004.05.005)
84. Faden AI, Demediuk P, Panter SS, Vink R. 1989 The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244, 798-800. (doi:10.1126/science.2567056)
85. Choi DW, Rothman SM. 1990 The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13, 171-182. (doi:10.1146/ annurev.ne.13.030190.001131)
86. Isokawa M, Levesque MF. 1991 Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices. Neurosci. Lett. 132, 212-216. (doi:10.1016/0304-3940(91)90304-C)
87. Hu NW, Ondrejcak T, Rowan MJ. 2012 Glutamate receptors in preclinical research on Alzheimer's disease: update on recent advances. Pharmacol. Biochem. Behav. 100, 855-862. (doi:10.1016/j.pbb. 2011.04.013)
88. Harada J, Sugimoto M. 1999 Activation of caspase-3 in beta-amyloid-induced apoptosis of cultured rat cortical neurons. Brain Res. 842, 311-323. (doi:10. 1016/S0006-8993(99)01808-9)
89. Jo J et al. 2011 Ab(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3b. Nat. Neurosci. 14, 545-547. (doi:10.1038/nn.2785)
90. Shankar GM et al. 2008 Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837-842. (doi:10.1038/nm1782)
91. Knobloch M, Mansuy IM. 2008 Dendritic spine loss and synaptic alterations in Alzheimer's disease. Mol. Neurobiol. 37, 73-82. (doi:10.1007/s12035-008-8018-z)
92. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. 2006 AMPAR removal underlies Ab-induced synaptic depression and dendritic spine loss. Neuron 52, 831-843. (doi:10. 1016/j.neuron.2006.10.035)
93. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. 2007 Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDAtype glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866-2875. (doi:10.1523/ JNEUROSCI.4970-06.2007)
94. Snyder EM et al. 2005 Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051-1058. (doi:10.1038/nn1503)
95. Olsen KM, Sheng M. 2012 NMDA receptors and BAX are essential for Abeta impairment of LTP. Sci. Rep. 2, 225. (doi:10.1038/srep00225)
96. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. 2009 APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981-989. (doi:10.1038/nature07767)
97. Simon DJ et al. 2012 A caspase cascade regulating developmental axon degeneration. J. Neurosci. 32, 17 540-17 553. (doi:10.1523/JNEUROSCI.3012-12.2012)
98. Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA. 2008 Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission. J. Neurophysiol. 99, 1515-1522. (doi:10.1152/jn.00598.2007)
99. Li H et al. 2008 Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 2169-2174. (doi:10.1073/pnas.0711647105)
100. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R. 2002 Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443-455. (doi:10.1016/S0092-8674(02)00897-8)
101. Qin Y et al. 2005 State-dependent Ras signaling and AMPA receptor trafficking. Genes Dev. 19, 2000-2015. (doi:10.1101/gad.342205)
102. Jurado S, Benoist M, Lario A, Knafo S, Petrok CN, Esteban JA. 2010 PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J. 29, 2827-2840. (doi:10.1038/emboj.2010.160)
103. Beurel E, Jope RS. 2006 The paradoxical pro-and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Progr. Neurobiol. 79, 173-189. (doi:10.1016/j.pneurobio. 2006.07.006)