Altered synaptic structure in the hippocampus in a mouse model of Alzheimer’s disease with soluble amyloid-β oligomers and no plaque pathology

Molecular Neurodegeneration

Dara L Dickstein²  Michelle E Ehrlich¹  Hannah Brautigam³  Frank Yuk²  Allison Sowa²  Merina Varghese²  Katherine A Price² 

[1] Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

关键词: Spines;    Dendrite;    Postsynaptic density;    Synapse;    APP E693Q;    Neuron;    Aβ oligomers;    Alzheimer’s disease;   

Others  :  1132688
DOI  :  10.1186/1750-1326-9-41

 received in 2014-06-23, accepted in 2014-08-27,  发布年份 2014

【 摘 要 】

Background

Mounting evidence suggests that soluble oligomers of amyloid-β (oAβ) represent the pertinent synaptotoxic form of Aβ in sporadic Alzheimer’s disease (AD); however, the mechanistic links between oAβ and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oAβ in mouse models that also possess insoluble fibrillar Aβ (fAβ), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oAβ on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q (“Dutch”) mouse model of AD, which develops intraneuronal accumulation of soluble oAβ with no detectable plaques in AD-relevant brain regions. We performed quantitative analyses of neuronal pathology, including dendrite morphology, spine density, and synapse ultrastructure in individual hippocampal CA1 neurons.

Results

When assessing neuronal morphology and complexity we observed significant alterations in apical but not in basal dendritic arbor length in Dutch mice compared to wild type. Moreover, Dutch mice exhibited a significant decrease in dendritic arborization with a decrease in dendritic length and number of intersections at 120 μm and 150 μm from the soma, respectively. We next examined synaptic parameters and found that while there were no differences in overall synaptic structure, Dutch mice displayed a significant reduction in the post-synaptic density (PSD) length of synapses on mushroom spines, in comparison to wild type littermates.

Conclusion

The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the Aβ oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oAβ first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration.

【 授权许可】

   
2014 Price et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Sakono M, Zako T: Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J 2010, 277:1348-1358.
• [2]Koffie RM, Hyman BT, Spires-Jones TL: Alzheimer’s disease: synapses gone cold. Mol Neurodegener 2011, 6:63. BioMed Central Full Text
• [3]Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE: Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2006, 103:5161-5166.
• [4]Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R: Memory deficits in APP23/Abca1+/- mice correlate with the level of Abeta oligomers. ASN Neuro 2009, 1(2):65-76.
• [5]O'Leary TP, Brown RE: Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer’s disease. Behav Brain Res 2009, 201:120-127.
• [6]Luebke JI, Weaver CM, Rocher AB, Rodriguez A, Crimins JL, Dickstein DL, Wearne SL, Hof PR: Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models. Brain Struct Funct 2010, 214:181-199.
• [7]Giannakopoulos P, Missonnier P, Kovari E, Gold G, Michon A: Electrophysiological markers of rapid cognitive decline in mild cognitive impairment. Front Neurol Neurosci 2009, 24:39-46.
• [8]Akram A, Christoffel D, Rocher AB, Bouras C, Kovari E, Perl DP, Morrison JH, Herrmann FR, Haroutunian V, Giannakopoulos P, Hof PR: Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease. Neurobiol Aging 2008, 29:1296-1307.
• [9]Bussiere T, Friend PD, Sadeghi N, Wicinski B, Lin GI, Bouras C, Giannakopoulos P, Robakis NK, Morrison JH, Perl DP, Hof PR: Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer’s disease. Neuroscience 2002, 112:75-91.
• [10]Glabe CG: Structural classification of toxic amyloid oligomers. J Biol Chem 2008, 283:29639-29643.
• [11]Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007, 27:2866-2875.
• [12]Haass C, Selkoe DJ: Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2007, 8:101-112.
• [13]LaFerla FM, Green KN, Oddo S: Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 2007, 8:499-509.
• [14]LaFerla FM, Green KN: Animal models of Alzheimer disease. Cold Spring Harb Perspect Med 2012, 2:1-13.
• [15]Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B: Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990, 248:1124-1126.
• [16]Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O’Dahl S, Nemens E, White JA, Sadovnick AD, Ball MJ, Kaye J, Warren A, McInnis M, Antonarakis SE, Korenberg JR, Sharma V, Kukull W, Larson E, Heston LL, Martin GM, Bird TD, Schellenberg GD: Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 1992, 51:998-1014.
• [17]Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J: Substitutions at codon 22 of Alzheimer’s abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 2000, 275:27110-27116.
• [18]Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H: A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol 2008, 63:377-387.
• [19]Scholl M, Wall A, Thordardottir S, Ferreira D, Bogdanovic N, Langstrom B, Almkvist O, Graff C, Nordberg A: Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology 2012, 79:229-236.
• [20]Gandy S, Simon AJ, Steele JW, Lublin AL, Lah JJ, Walker LC, Levey AI, Krafft GA, Levy E, Checler F, Glabe C, Bilker WB, Abel T, Schmeidler J, Ehrlich ME: Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-beta oligomers. Ann Neurol 2010, 68:220-230.
• [21]Wang Z, Natte R, Berliner JA, van Duinen SG, Vinters HV: Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells. Stroke 2000, 31:534-538.
• [22]Ozawa K, Tomiyama T, Maat-Schieman ML, Roos RA, Mori H: Enhanced Abeta40 deposition was associated with increased Abeta42-43 in cerebral vasculature with Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D). Ann N Y Acad Sci 2002, 977:149-154.
• [23]Nishitsuji K, Tomiyama T, Ishibashi K, Kametani F, Ozawa K, Okada R, Maat-Schieman ML, Roos RA, Iwai K, Mori H: Cerebral vascular accumulation of Dutch-type Abeta42, but not wild-type Abeta42, in hereditary cerebral hemorrhage with amyloidosis, Dutch type. J Neurosci Res 2007, 85:2917-2923.
• [24]Harris KM, Kater SB: Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 1994, 17:341-371.
• [25]Carlisle HJ, Kennedy MB: Spine architecture and synaptic plasticity. Trends Neurosci 2005, 28:182-187.
• [26]Segal M: Dendritic spines and long-term plasticity. Nat Rev Neurosci 2005, 6:277-284.
• [27]Brautigam H, Steele JW, Westaway D, Fraser PE, St George-Hyslop PH, Gandy S, Hof PR, Dickstein DL: The isotropic fractionator provides evidence for differential loss of hippocampal neurons in two mouse models of Alzheimer’s disease. Mol Neurodegener 2012, 7:58. BioMed Central Full Text
• [28]Tackenberg C, Ghori A, Brandt R: Thin, stubby or mushroom: spine pathology in Alzheimer’s disease. Curr Alzheimer Res 2009, 6:261-268.
• [29]Harris KM, Jensen FE, Tsao B: Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 1992, 12:2685-2705.
• [30]Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120:885-890.
• [31]Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985, 82:4245-4249.
• [32]Gotz J, Ittner LM, Schonrock N, Cappai R: An update on the toxicity of Abeta in Alzheimer’s disease. Neuropsychiatr Dis Treat 2008, 4:1033-1042.
• [33]Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O’Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL: Imaging of amyloid beta in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol 2008, 7:129-135.
• [34]Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B: Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004, 55:306-319.
• [35]Jack CR Jr, Wiste HJ, Knopman DS, Vemuri P, Mielke MM, Weigand SD, Senjem ML, Gunter JL, Lowe V, Gregg BE, Pankratz VS, Petersen RC: Rates of beta-amyloid accumulation are independent of hippocampal neurodegeneration. Neurology 2014, 82:1605-1612.
• [36]Sokolow S, Henkins KM, Williams IA, Vinters HV, Schmid I, Cole GM, Gylys KH: Isolation of synaptic terminals from Alzheimer’s disease cortex. Cytometry A 2012, 81:248-254.
• [37]Habicht G, Haupt C, Friedrich RP, Hortschansky P, Sachse C, Meinhardt J, Wieligmann K, Gellermann GP, Brodhun M, Gotz J, Halbhuber KJ, Röcken C, Horn U, Fändrich M: Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Abeta protofibrils. Proc Natl Acad Sci U S A 2007, 104:19232-19237.
• [38]Baumketner A, Krone MG, Shea JE: Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-beta protein. Proc Natl Acad Sci U S A 2008, 105:6027-6032.
• [39]Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ: Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 2002, 277:32046-32053.
• [40]Melchor JP, Van Nostrand WE: Fibrillar amyloid beta-protein mediates the pathologic accumulation of its secreted precursor in human cerebrovascular smooth muscle cells. J Biol Chem 2000, 275:9782-9791.
• [41]Murakami K, Irie K, Morimoto A, Ohigashi H, Shindo M, Nagao M, Shimizu T, Shirasawa T: Neurotoxicity and physicochemical properties of Abeta mutant peptides from cerebral amyloid angiopathy: implication for the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. J Biol Chem 2003, 278:46179-46187.
• [42]Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M: Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 2004, 7:954-960.
• [43]Ji J, Maren S: Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear. Learn Mem 2008, 15:244-251.
• [44]Farovik A, Dupont LM, Eichenbaum H: Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events. Learn Mem 2010, 17:12-17.
• [45]Gil N, Josman N: Memory and metamemory performance in Alzheimer’s disease and healthy elderly: the Contextual Memory Test (CMT). Aging (Milano) 2001, 13:309-315.
• [46]Hausser M, Spruston N, Stuart GJ: Diversity and dynamics of dendritic signaling. Science 2000, 290:739-744.
• [47]Kampa BM, Letzkus JJ, Stuart GJ: Dendritic mechanisms controlling spike-timing-dependent synaptic plasticity. Trends Neurosci 2007, 30:456-463.
• [48]Stuart G, Spruston N, Sakmann B, Hausser M: Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci 1997, 20:125-131.
• [49]Henry BI, Langlands TA, Wearne SL: Fractional cable models for spiny neuronal dendrites. Phys Rev Lett 2008, 100:128103.
• [50]Ferrer I, Gullotta F: Down’s syndrome and Alzheimer’s disease: dendritic spine counts in the hippocampus. Acta Neuropathol 1990, 79:680-685.
• [51]Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML: Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 2004, 33:377-387.
• [52]Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT: Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 2005, 25:7278-7287.
• [53]Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL: Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 2007, 27:796-807.
• [54]Parameshwaran K, Sims C, Kanju P, Vaithianathan T, Shonesy BC, Dhanasekaran M, Bahr BA, Suppiramaniam V: Amyloid beta-peptide Abeta(1–42) but not Abeta(1–40) attenuates synaptic AMPA receptor function. Synapse 2007, 61:367-374.
• [55]Parameshwaran K, Dhanasekaran M, Suppiramaniam V: Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 2008, 210:7-13.
• [56]Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y: Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci 2004, 24:7648-7653.
• [57]Harris KM, Weinberg RJ: Ultrastructure of synapses in the mammalian brain. Cold Spring Harb Perspect Biol 2012, 4:1-31.
• [58]Peters A, Palay SL, Webster H: The fine structure of the nervous system : neurons and their supporting cells. 3rd edition. New York: Oxford University Press; 1991.
• [59]Jones DG, Harris RJ: An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: perforated synapses revisited. Rev Neurosci 1995, 6:177-219.
• [60]Geinisman Y: Structural synaptic modifications associated with hippocampal LTP and behavioral learning. Cereb Cortex 2000, 10:952-962.
• [61]Isaac JT, Nicoll RA, Malenka RC: Evidence for silent synapses: implications for the expression of LTP. Neuron 1995, 15:427-434.
• [62]Geinisman Y, Ganeshina O, Yoshida R, Berry RW, Disterhoft JF, Gallagher M: Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol Aging 2004, 25:407-416.
• [63]Ganeshina O, Berry RW, Petralia RS, Nicholson DA, Geinisman Y: Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities. J Comp Neurol 2004, 468:86-95.
• [64]Nusser Z, Lujan R, Laube G, Roberts JD, Molnar E, Somogyi P: Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 1998, 21:545-559.
• [65]Petralia RS, Esteban JA, Wang YX, Partridge JG, Zhao HM, Wenthold RJ, Malinow R: Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat Neurosci 1999, 2:31-36.
• [66]Racca C, Stephenson FA, Streit P, Roberts JD, Somogyi P: NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci 2000, 20:2512-2522.
• [67]Takumi Y, Ramirez-Leon V, Laake P, Rinvik E, Ottersen OP: Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci 1999, 2:618-624.
• [68]Gu Z, Liu W, Yan Z: {beta}-Amyloid impairs AMPA receptor trafficking and function by reducing Ca2+/calmodulin-dependent protein kinase II synaptic distribution. J Biol Chem 2009, 284:10639-10649.
• [69]Poncer JC, Esteban JA, Malinow R: Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II. J Neurosci 2002, 22:4406-4411.
• [70]Hayashi Y, Shi SH, Esteban JA, Piccini A, Poncer JC, Malinow R: Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 2000, 287:2262-2267.
• [71]Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA: The case for soluble Abeta oligomers as a drug target in Alzheimer’s disease. Trends Pharmacol Sci 2013, 34:261-266.
• [72]Pozueta J, Lefort R, Shelanski ML: Synaptic changes in Alzheimer’s disease and its models. Neuroscience 2013, 251:51-65.
• [73]Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D: Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 2001, 276:21562-21570.
• [74]Dudal S, Krzywkowski P, Paquette J, Morissette C, Lacombe D, Tremblay P, Gervais F: Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging 2004, 25:861-871.
• [75]Steele JW, Brautigam H, Short JA, Sowa A, Shi M, Yadav A, Weaver CM, Westaway D, Fraser PE, St George-Hyslop PH, Gandy S, Hof PR, Dickstein DL: Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer’s disease mouse model. J Comp Neurol 2014, 522:2319-2335.
• [76]Dickstein DL, Brautigam H, Stockton SD Jr, Schmeidler J, Hof PR: Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau. Brain Struct Funct 2010, 214:161-179.
• [77]Olichney JM, Hansen LA, Galasko D, Saitoh T, Hofstetter CR, Katzman R, Thal LJ: The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer’s disease and Lewy body variant. Neurology 1996, 47:190-196.
• [78]Tyan SH, Shih AY, Walsh JJ, Maruyama H, Sarsoza F, Ku L, Eggert S, Hof PR, Koo EH, Dickstein DL: Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cell Neurosci 2012, 51:43-52.
• [79]Sholl DA: Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 1953, 87:387-406.
• [80]Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR: Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 2008, 507:1141-1150.
• [81]Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH: Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 2006, 16:313-320.
• [82]Wearne SL, Rodriguez A, Ehlenberger DB, Rocher AB, Henderson SC, Hof PR: New techniques for imaging, digitization and analysis of three-dimensional neural morphology on multiple scales. Neuroscience 2005, 136:661-680.
• [83]Rodriguez A, Ehlenberger DB, Hof PR, Wearne SL: Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images. Nat Protoc 2006, 1:2152-2161.
• [84]Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL: Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 2008, 3:e1997.
• [85]Bloss EB, Puri R, Yuk F, Punsoni M, Hara Y, Janssen WG, McEwen BS, Morrison JH: Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiol Aging 2013, 34:200-210.
• [86]Janssen WG, Vissavajjhala P, Andrews G, Moran T, Hof PR, Morrison JH: Cellular and synaptic distribution of NR2A and NR2B in macaque monkey and rat hippocampus as visualized with subunit-specific monoclonal antibodies. Exp Neurol 2005, 191(Suppl 1):S28-44.
• [87]Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH: Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 2010, 30:7507-7515.
• [88]Hara Y, Rapp PR, Morrison JH: Neuronal and morphological bases of cognitive decline in aged rhesus monkeys. Age (Dordr) 2012, 34:1051-1073.
• [89]Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW, Svoboda K: Transient and persistent dendritic spines in the neocortex in vivo. Neuron 2005, 45:279-291.
• [90]Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H: Structure-stability-function relationships of dendritic spines. Trends Neurosci 2003, 26:360-368.