Cereb. cortex 2009-knafo-586-92


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Cereb. cortex 2009-knafo-586-92

  1. 1. Cerebral Cortex March 2009;19:586--592doi:10.1093/cercor/bhn111Advance Access publication July 16, 2008Widespread Changes in Dendritic Spines S. Knafo1, L. Alonso-Nanclares1, J. Gonzalez-Soriano2, P. Merino- Serrais1, I. Fernaud-Espinosa1, I. Ferrer3 and J. DeFelipe1in a Model of Alzheimer’s Disease 1 Instituto Cajal (CSIC), 28002 Madrid, Spain, 2Department of Anatomy, Faculty of Veterinary Medicine, Complutense University, 28040 Madrid, Spain and 3Institut Neuropatologı´ a, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de LLobregat, 08907 Barcelona, SpainThe mechanism by which dementia occurs in patients with of the axo-spinous synapse (Zuo et al. 2005). Importantly,Alzheimer’s disease (AD) is not known. We assessed changes in recent evidence indicates that spine heads are targets of Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010hippocampal dendritic spines of APP/PS1 transgenic mice that oligomeric Ab (Lacor et al. 2007). Therefore, spine headaccumulate amyloid beta throughout the brain. Three-dimensional morphology may link Ab pathology and synaptic dysfunction.analysis of 21 507 dendritic spines in the dentate gyrus, a region We individually injected granular neurons in the dentatecrucial for learning and memory, revealed a substantial decrease in gyrus with a fluorescent dye and counterstained Ab plaquesthe frequency of large spines in plaque-free regions of APP/PS1 with thiflavin-s. We measured the head volume and neck lengthmice. Plaque-related dendrites also show striking alterations in in 3 dimensions of thousands of individual dendritic spines thatspine density and morphology. However, plaques occupy only 3.9% have been scanned by confocal microscopy. Our results showof the molecular layer volume. Because large spines are considered that plaques substantially affect dendrites and spines. Impor-to be the physical traces of long-term memory, widespread tantly, we also determined that plaque-free regions of APP/PS1decrease in the frequency of large spines likely contributes to the mice are affected. These regions are very deficient in largecognitive impairments observed in this AD model. spines, although spine density is conserved. We suggest that widespread decreased frequency of large spines contributes toKeywords: Alzheimer’s disease, confocal microscopy, dementia, dentate the cognitive deficits found in this AD model.gyrus, transgenic mice Materials and MethodsIntroduction Mice The mouse line used in this study (N = 9, age 12--14 months) expressedOne of the primary pathological characteristics of Alzheimer’s a Mo/Hu APP695swe construct in conjunction with the exon-9--deleteddisease (AD) is the presence of amyloid plaques, formed by variant of human presenilin 1 (PS1-dE9) (Scheuner et al. 1996). Age-aggregated b-amyloid (Ab) peptides. In mice, the expression of matched littermates served as controls (N = 9). The experiments werechimeric mouse/human amyloid precursor protein (Mo/ approved by the ethical institutional committee according to NationalHuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), Institutes of Health guidelines.proteins that are both involved in familial forms of AD, lead toan early amyloid pathology. These double transgenic mice Intracellular Injections(APP/PS1) are often used as an animal model of AD, although The preparation of brains for intracellular injections is detailed in thethey do not develop the extensive neuronal loss or neurofi- supplemental methods. A total of 235 granular neurons from Tg– mice and 462 neurons from APP/PS1 mice were microinjected individuallybrillary changes typical in AD (Irizarry et al. 1997). Neverthe- with Alexa594 (Invitrogen, Eugene, OR, Fig. 1a,b). After injection,less, this mouse model is used to investigate the effect of Ab plaques were counterstained with thioflavin-s. Image acquisition andoverproduction and deposition on brain circuitry. processing are described in the supplemental information. All Although Ab plaques have been associated with changes in morphological measurements were performed on stacks that did notneurite morphology and dendritic spine density (Tsai et al. contain images of plaques (see supplemental information).2004; Spires et al. 2005), there is a poor correlation betweenplaque load and cognitive functions (Terry et al. 1991), raising Spine Morphologydoubts as to whether the accumulation of Ab plaques in the Imaris 5.0 (Bitplane AG, Zurich, Switzerland) was used to measurebrain induces AD. Nevertheless, morphological studies on AD spine head volume and neck length. A solid surface that exactlymodels and patients have so far focused on the structural matched the contours of the head was constructed for each spine (Isosurface module, Fig. 1j--m, Supplemental Fig. 1b,c). For details, seechanges occurring within or proximal to plaques (Tsai et al. supplemental methods.2004; Spires et al. 2005). Dendritic spines represent the major postsynaptic elementsof excitatory synapses in the cerebral cortex (Gray 1959) and Unbiased Stereology The number of labeled plaques was estimated by optical fractionator.are fundamental to memory, learning and cognition (Lamp- The volume of plaques was estimated with the Nucleator probe (Mollerrecht and LeDoux 2004). Dendritic spines undergo remarkable et al. 1990), as described in the supplemental methods.activity-dependent structural changes (Lang et al. 2004; Tsaiet al. 2004). The spine head size influences spine motility and Statisticsstability. Spine head size determines the probability that a spine For all measured morphological parameters, values were averaged tobears a synapse (Arellano et al. 2007). Furthermore, there is give a cell mean. Neurons from each animal were averaged for ana strong correlation between spine head size and the strength animal mean. Normality was tested using the Kolmogorov--Smirnov test.Ó The Author 2008. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oxfordjournals.org
  2. 2. Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010Figure 1. Intracellular injections and methodology. Panoramic confocal composite (103) views of the dentate gyrus, showing Alexa594 injected neurons and thioflavin-s positiveplaques in a TgÀ mouse (a) and an APP/PS1 mouse (b). Representative projection images of granular neurons from a TgÀ mouse (c) and from an APP/PS1 mouse (d). (e) Anexample of a dendrite passing within a plaque. (f) An example of a dendrite in contact with a plaque. (g--i) The method used to distinguish dendrites and spines within plaques. (g)A plaque suspected to contain a dendrite due to the rotation of its 3D image. (h) The plaque surface is marked with the aid of the IsoSurface tool of Imaris software. (i) The voxelsoutside the surface are set to zero, leaving only the dendritic segment within the plaque. This process was performed after measurements of the spine head and neck that weredone blindly. (j, k) The method used for spine head volume measurements. (j) A solid surface that exactly matched the contours of the head was constructed for each spine (k). (l,m) Amplified image of a short dendritic segment with (l) and without (m) the marked spine heads. Stacks used for images (e--m) were taken with a 633 glycerol objective, NA1.3, electronic zoom 3.2). Scale bar, (a, b) 150 lm, (c, d) 40 lm, (e) 6 lm, (f, j, k) 4 lm, (g--i) 10 lm, (l, m) 2.5 lm.Because our values had Gaussian distributions, a 2-tailed unpaired t-test We examined 1,589 amyloid plaques and 462 APP/PS1was used to test for overall effect. When more than 2 groups were injected granular neurons by confocal microscopy (633,compared, a one-way ANOVA was used, followed by the Newman-- glycerol, zoom 3.2, Fig. 1a--d). We encountered 52 dendritesKeuls multiple comparison post hoc test. Data are presented as themean ± SE. that passed within plaques and 32 dendrites that contacted a plaque but did not pass within it (Fig. 1e,f). Typical plaques, positive for thiflavin-s, consisted of a core, surrounded byResults a diffuse ring of decreasing density (Cruz et al. 1997). The dendrites passing within plaques were always located in theAltered Spine Density in Plaque-Related Dendrites diffuse peripheral ring (Fig. 1e,g--i).We used APP/PS1 mice at the age of 12--14 months. Because Dendrites were categorized according to their location withtransgenic mice of this age range show cognitive decline (Malm respect to Ab plaques (Fig. 2a). Categories included: 1)et al. 2007) and deficits in cortical plasticity (Battaglia et al. dendrites from transgene-negative (control) mice (Tg–), 2)2007), our working hypothesis was that these mice would dendrites located in a plaque-free area throughout their lengthexhibit substantial changes in their dendritic spines. Although (Plaque-free), 3) dendrites that passed within a plaque (Pla-the toxic effects of Ab plaques on dendritic spines have been que), and 4) dendrites in contact with a plaque edge (part ofdocumented before in the neocortex (Tsai et al. 2004; Spires the dendrite located within 0.2 lm from the plaque edge, aset al. 2005), we hypothesized that in the dentate gyrus, Ab measured 3D) but did not pass through it (In contact, seeplaques would also have a tropic effect, given the extensive Supplemental Fig. 1a,b).sprouting in the hippocampal molecular layer seen in an AD Spine density was significantly different among the 4model (Masliah et al. 1991). categories of dendrites (P = 0.019, one-way ANOVA, Fig. 2b). Cerebral Cortex March 2009, V 19 N 3 587
  3. 3. Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010Figure 2. Pronounced changes in dendritic spine density in plaque-related dendrites. (a) Representative projection images of dendrites from TgÀ and APP/PS1 mice (633,glycerol). Note the variation in spine density among dendrites. TgÀ, dendrite from a control mouse; PF, dendrite located in plaque-free region of APP/PS1 mouse; IC, dendrite ofwhich a part is in contact with a plaque; P, dendrite that passes within a plaque, with and without the green channel that contains the plaque image. (b) Spine density wassignificantly decreased in Plaque dendrites and increased for In contact dendrites. Note that spine density is similar in TgÀ mice and plaque-free areas. (c) Cumulative frequencycurves show shifts in spine density of plaque-related dendrites. (d) Spine density as a function of distance from soma is similar in TgÀ mice and APP/PS1 mice in plaque-freeregions. (e) For each plaque-related dendritic segment, the distance of the plaque from the soma was measured, and the ratio between spine density for the segment and theaverage spine density for the same distance in TgÀ mice was calculated. Scale bar, 3 lm. *P 0.05, **P 0.01, ***P 0.001.In Plaque dendrites, spine density was significantly lower than (P = 0.0016, one-way ANOVA, Fig. 3b). Average head volumein other categories of dendrites (0.950 ± 0.075 spines/lm, N = was significantly lower (P < 0.05, Newman--Keuls multiple9, P < 0.001, Newman--Keuls multiple comparison test). Spine comparison post hoc test) in Plaque-free spines (0.080 ± 0.004density for In contact dendrites was significantly higher than in lm3; 9913 spines) and for In contact spines (0.076 ± 0.006; 443other categories of dendrites (2.05 ± 0.13, N = 9, P < 0.001). spines), when compared with Plaque spines (0.107 ± 0.008;Spine density for Plaque-free dendrites (1.521 ± 0.047, N = 9) 474 spines), and control (0.103 ± 0.006; 10 677 spines).was not significantly different than control (Tg–) dendrites Although the average head volumes for control spines and(1.410 ± 0.052, N = 9). Plaque spines were similar, frequency analysis revealed that the Spine density normally changes as a function of distance within-groups distribution was substantially different betweenfrom the soma. Sholl analysis can be used to examine spine the 2 groups (Fig. 3c). Within plaques, there was a 36%density at different distances from the soma. Sholl analysis decrease in the prevalence of small-headed spines (headrevealed that spine density for Plaque-free dendrites was volume < 0.05 lm3) and a 40% increase in the prevalence ofsimilar to control (Tg–) dendrites over their entire length spines with a medium-size head (head volume 0.05--0.1 lm3),(Fig. 2d). Spine density for each segment located within or in compared with control spines (Fig. 3c). The prevalence ofcontact with a plaque was compared with the average spine large-headed spines (large spines, head volume > 0.1 lm3) wasdensity at same distance from soma in Tg– mice. We found similar for both dendritic types (Fig. 3c). Our measurementsa decrease of 37.21 ± 6.03% in spine density within plaques show that large spines represent 23% of Tg– dentate gyrus(P < 0.0001, t-test) and a 37.77 ± 15.77% increase in spine spines but only 14.4% of the plaque-free APP/PS1 spines. Thisdensity of In contact dendrites (P = 0.01, Fig. 2e). Thus, we implies a decrease of 38% in the prevalence of large spines infound considerable sprouting of spines in dendrites contacting the plaque-free regions of APP/PS1 mice. When compared withAb plaques, whereas there was a loss of spines in dendrites control mice, there was a 52% decrease in the prevalence ofpassing through Ab plaques. large spines in dendrites contacting plaques (Fig. 3d). We also divided the granular neurons into neurons that have come intoDecreased Frequency of Large Spines in Plaque-Free contact with or passed within plaques at some point along theirAreas length and those that never contacted a plaque. An analysis ofSpine head volume and neck length were measured in 3 the spine head volume revealed that spines located in plaque-dimensions in confocal image stacks. Head volume was free regions had a similar head volume although they arise fromsignificantly different among the 4 categories of dendrites different neuronal types (Supplemental Fig. 2).588 Widespread Changes in Dendritic Spines in a Model of AD d Knafo et al.
  4. 4. Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010Figure 3. Changes in spine morphology occur both within and outside Ab plaques. (a) Maximum projection confocal images (633, glycerol) of representative dendrites. Notethe great variation in spine morphology among groups. Scale bar, 1.5 lm. (b) Decreased average head volume for spines located outside plaques. (c) Cumulative frequency plotsshowing the distribution of spine head volumes. (d) The frequency of large spines is substantially reduced outside plaques. (e) Bar graphs showing that spines located withinplaques have longer necks. (f) Cumulative frequency curves showing the distribution of neck lengths. (g) On the left, density of plaques in the molecular layer of the dentate gyrus.On the right, the fraction of the molecular layer volume occupied by plaques. *P 0.05, **P 0.01, ***P 0.001. Significant differences in average spine neck length, as was then determined, using unbiased stereology, the total numbermeasured manually in 3 dimensions, were found among of plaques and their volume in the molecular layer. From this,dendritic categories (P < 0.0001, one-way ANOVA, Fig. 3e,f). we calculated the total volume occupied by plaques.Plaque spines had a longer neck (0.634 ± 0.028 lm, P < 0.001, The estimated total number of molecular layer plaques perNewman--Keuls Multiple Comparison Test) than control spines mouse in one hemisphere was 609.9 ± 37.14 (range 555--756(0.443 ± 0.012) and Plaque-free spines (0.455 ± 0.035). Necks plaques/mouse, N = 5 mice). The density of plaques in theof In contact spines showed intermediate length (0.540 ± inner molecular layer (IML) was 3.00 ± 0.25 plaques/100 lm3,0.026) and were significantly different from other dendritic whereas the density of plaques in the middle/outer molecularcategories (P < 0.05). layer (M/OML) was 5.99 ± 0.39 plaques/100 lm3 (Fig. 3g). This observation supports the finding that plaques in the dentateAmyloid Plaques Occupy a Small Fraction of the gyrus of AD brains have a strong tendency to line up in theMolecular Layer Volume molecular layer, approximately two-thirds of the way fromWe have described remarkable changes within and near the top of the hippocampal fissure (Crain and Burger 1989).plaques that can affect local synaptic circuits. To quantitatively The average plaque volume was 5657 ± 1488 lm3 in the IMLdetermine the impact of plaques on the dentate gyrus and 8719 ± 1109 lm3 in the M/OML (P > 0.05). The estimatedconnectivity, we immunocytochemically stained Ab plaques volume occupied by Ab plaques was 1.59 ± 0.39% in IML andin sections of APP/PS1 brains, taken from the same mice. We 5.15 ± 0.60% in the M/OML (Fig. 3g). The volume occupied by Cerebral Cortex March 2009, V 19 N 3 589
  5. 5. Ab plaques in the entire molecular layer was 3.9 ± 0.4%. These explained by alterations to the ratio of spine formation toresults suggest that under our experimental conditions, Ab elimination, leading a higher proportion of aspiny dendrites asplaques occupy a relatively small fraction of the total molecular observed in the cortex of Tg2576 mice (Spires-Jones et al. 2007).layer volume. In contrast to our observations, a recent study reported a reduction in spine density in the hippocampus of APP mice before and after the appearance of plaques (Jacobsen et al.Discussion 2006). This discrepancy could be related to the fact thatThe current study shows that plaque-free regions of the a different mouse model was used in this study (APP vs. APP/dentate gyrus in APP/PS1 mice are deficient in large spines and PS1), as well as a different staining method (Golgi staining vs.that dendritic spines are also affected locally by Ab plaques. intracellular injections), and a different method for quantifica-However, under our experimental conditions, plaques occupy tion (quantification of short dendritic segments vs. fulla volume below 4% of the dentate gyrus molecular layer. dendritic lengths). A decrease in spine density in the hippocampus of aged APP/PS1 mice described previouslyDecreased Frequency of Large Spines may Imply Loss of (Moolman et al. 2004) could be explained by including the Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010Memory dendrites located within plaques in the analysis, because spineDendritic spine heads bear the vast majority (90%) of density is significantly lower at these sites (see Tsai et al. 2004excitatory synapses in the central nervous system (Gray and Fig. 1b). Other studies reported a decrease in synaptic1959). They undergo remarkable activity-dependent structural density in AD models (Dong et al. 2007; Priller et al. 2007).changes (Lang et al. 2004; Knafo et al. 2005) and are targets of However, although we quantified dendritic spines, these earlieroligomeric Ab (Lacor et al. 2007). Although morphological studies quantified synapses regardless of their location (spinechanges within Ab plaques can affect local synaptic circuits, or dendritic shaft). Thus, the possibility that the decrease inbecause plaques occupy a minor fraction of the dentate gyrus synaptic density arises from the loss of shaft synapses cannot bevolume, widespread changes outside plaques are more likely to excluded.contribute to the synaptic and cognitive impairments found in The increased spine density in the vicinity of the plaques canAPP/PS1 mice (Battaglia et al. 2007; Malm et al. 2007). be explained by the release of neurotrophic factors, such as Large spines contain polyribosomes that locally regulate brain-derived neurotrophic factor by astrocytes that typicallyprotein synthesis and are surrounded by perisynaptic astroglial surround Ab plaques (Mandybur 1989; Saha et al. 2006). It isprocesses that regulate local glutamate and Ca2+ levels (Ostroff tempting to speculate that the growth of new spines in theet al. 2002; Haber et al. 2006; Witcher et al. 2007). Large spines vicinity of the plaques is an attempt by the diseased brain topersist for months in the mouse cerebral cortex (Grutzendler compensate for the loss of spines within them.et al. 2002; Trachtenberg et al. 2002). Large spines bearsynapses exceptionally stable (Bourne and Harris 2007). Large Ab Plaques Protect Large Spinesspines are also enriched with a-amino-3-hydroxy-5-methyl-4- Notably, the prevalence of large spines within plaques and inisoxazolepropionic acid receptors (Matsuzaki et al. 2001), Tg– control mice was similar. Although we observed a 36%which make their synapses functionally stronger (Matsuzaki decrease in spine density within plaques, this decrease waset al. 2001; Nimchinsky et al. 2004; Ashby et al. 2006). mainly due to a decrease in the frequency of spines with smallMoreover, large spines are formed after synaptic potentiation heads (see Fig. 3c). This may imply that plaques serve asin the dentate gyrus (Bourne and Harris 2007) and in CA1 a protective microenvironment for large spines. The persis-region (Lang et al. 2004; Matsuzaki et al. 2004). Thus, large tence of large spines within plaques can contribute to the weakspines were proposed to act as physical traces of long-term correlation between the quantity of amyloid deposition andmemory (Kasai et al. 2003; Bourne and Harris, 2007). dementia (Katzman et al. 1988). The sprouting of spines in Given that large spines in the dentate gyrus bear stable dendrites of immediate proximity to plaques is anothersynapses that form part of the hippocampal memory storage observation that can explain the same phenomenon. Thesesystem (Bontempi et al. 1999), a decrease in the frequency of dendrites possess predominantly small-headed spines. How-large spines should lead to the memory loss seen in APP/PS1 ever, it remains to be determined whether spines within andmice (Malm et al. 2007). Nevertheless, it is possible that the near plaque bear synapses and if these synapses are functional.decreased frequency of large dendritic spines is secondary to To summarize, we suggest that the substantial alterations inthe cognitive impairments observed in APP/PS1 mice, and dendritic spines within plaques most likely affect local synapticthose in plasticity (Fiala et al. 2002). Both memory and synaptic connections. However, it is difficult to determine whetherplasticity are disrupted in AD models and patients (Nalbantoglu these changes contribute to the cognitive impairment seen inet al. 1997), potentially preventing plasticity-related spine these mice. Because the plaque load and cognitive impairmentenlargement (Lang et al. 2004). in AD patients does not appear to be correlated (Terry et al. 1991), it is possible that the contribution of plaques to cognitiveDendritic Spines are Altered by Ab Plaques impairment is relatively insignificant. Therefore, we propose thatWe report here that dendrites that pass through a plaque lose the widespread changes in plaque-free regions, corresponding tospines, whereas dendrites that contact a plaque gain spines. more than 95% of the neuropil, may have a more importantDendrites located in plaque-free areas show a spine density influence on the cognitive status of these mice.similar to those of Tg– mice but have a decreased frequency oflarge spines. Decreased spine density within plaques andsprouting of spines in the vicinity of plaques have been Supplementary Materialdocumented in the neocortex (Ferrer et al. 1990; Tsai et al. Supplementary material can be found at: http://www.cercor.2004). The decreased spine density within plaques could be oxfordjournals.org/590 Widespread Changes in Dendritic Spines in a Model of AD d Knafo et al.
  6. 6. Funding Knafo S, Libersat F, Barkai E. 2005. Olfactory learning-induced morphological modifications in single dendritic spines of youngCIBERNED grant, Fundacion Caixa (BM05-47-0); The EU 6th rats. Eur J Neurosci. 21:2217--2226.Framework Program (PROMEMORIA LSHM-CT-2005-512012); Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT,the Spanish Ministry of Science and Technology (grant Wood M, Viola KL, Klein WL. 2007. A{beta} Oligomer-inducedBFU2006-13395); and Juan de la Cierva Program of the Ministry aberrations in synapse composition, shape, and density provideof Science and Technology fellowship to S.K. a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 27:796--807. Lamprecht R, LeDoux J. 2004. Structural plasticity and memory. Nat RevNotes Neurosci. 5:45--54. Lang C, Barco A, Zablow L, Kandel ER, Siegelbaum SA, Zakharenko SS.We thank Gabriel Santpere, Ana Martinez, and Gerard Muntane for 2004. 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