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. 2009 Nov 23;588(Pt 1):107–116. doi: 10.1113/jphysiol.2009.178905

Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling

R Anne McKinney 1
PMCID: PMC2821552  PMID: 19933758

Abstract

In the central nervous system, most excitatory synapses occur on dendritic spines, which are small protrusions from the dendritic tree. In the mature cortex and hippocampus, dendritic spines are heterogeneous in shape. It has been shown that the shapes of the spine can affect synapse stability and synaptic function. Dendritic spines are highly motile structures that can undergo actin-dependent shape changes, which occur over a time scale ranging from seconds to tens of minutes or even days. The formation, remodelling and elimination of excitatory synapses on dendritic spines represent ways of refining the microcircuitry in the brain. Here I review the current knowledge on the effects of modulation of AMPA and NMDA ionotropic glutamate receptors on dendritic spine formation, motility and remodelling.

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R. Anne McKinney (McGill University, Montreal, Canada) received her BSc (Hons) in Biomedical Sciences and her DPhil in Neuroscience from the University of Ulster, Coleraine, Northern Ireland, in 1992. She completed her postdoctoral fellowship and had her first independent research group in the Department of Neurophysiology, Brain Research Institute, University of Zurich, Switzerland. She is currently an Associate Professor in the Department of Pharmacology and Therapeutics, McGill University. Her principle research interest is the mechanisms involved in development, maintenance and plasticity of excitatory synapses in the CNS, during physiological and pathological conditions such as epilepsy and autism. She has won many awards for her work including in 1999 the Pfizer Research Prize in Basic Neuroscience and in 2009 the Hugh and Helene McPherson Memorial Award.

l-Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system (CNS), acting through both ionotropic and metabotropic receptors. It has been well documented to play a major role in basal excitatory synaptic transmission and in more recent years, it has been shown to be important in many forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie learning and memory (Rumpel et al. 2005; Morris, 2006; Pastalkova et al. 2006; Whitlock et al. 2006). The main subtypes of glutamate receptors expressed at glutamatergic synapses are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-asparate (NMDA) receptors. The activation of AMPA-type glutamate receptors provides most of the synaptic currents mediating excitatory postsynaptic potentials (EPSPs). NMDA receptor subtypes can initiate lasting changes in the strength of excitatory synaptic transmission that is thought to underlie learning and memory (Malenka & Nicoll, 1993; Huang & Pallas, 2001) and plays a major role in the refinement and the pruning of synaptic circuits (Lüthi et al. 2001; Adesnik et al. 2008).

In the mature CNS, the majority of excitatory synapses occur on dendritic spines, which are small, approximately 1 μm in length, protrusions of the dendritic tree (Yuste & Bonhoeffer, 2004). Dendritic spines receive excitatory glutamatergic input directly from apposing presynaptic terminals (Bourne & Harris, 2008). Dendritic spines are heterogeneous in shape and size, in particular in the mammalian cortex and hippocampus (Fig. 1), and have been classified as mushroom, thin and stubby spines, based on the length of their neck and the size of their spine head (Jones & Powell, 1969; Peters & Kaiserman-Abramof, 1970; Harris et al. 1992).

Figure 1. Diversity of spine shape.

Figure 1

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A, three-dimensional tertiary portion of the dendritic tree of a CA1 pyramidal cell from a green fluorescent protein-expressing mouse brain. Dendritic spines are classified into three main types: short, stubby spines (<0.5 μm in length) (B), mushroom-type spines, consisting of a short neck and mushroom-shaped head (C), or thin, long spines with an elongated neck and small head (D). Scale bar, 1 μm.

Occupying a small region of the dendritic spine membrane directly opposing the contacting presynaptic terminal is the postsynaptic density (PSD), an electron-dense protein matrix which contains glutamate receptors and various membrane proteins which are anchored to cytoskeletal scaffolding molecules (Okabe, 2007; Sheng & Hoogenraad, 2007; Newpher & Ehlers, 2009). Within the PSD, most excitatory synaptic transmission occurs through NMDA and AMPA receptors. Different glutamate receptors have been shown through electron microscopy studies to be predominately located in different regions of the postsynaptic membrane (Baude et al. 1995; Kharazia et al. 1996; Nusser et al. 1998; Takumi et al. 1999a; Perez-Otano et al. 2006; Masugi-Tokita et al. 2007). For example, AMPA receptors are at the edge of the PSD, whereas NMDA receptors are often centrally located within the PSD (Kharazia & Weinberg, 1997). Furthermore, subcellular immunogold labelling of NMDA and AMPA receptor subunits provides high resolution electron microscopy visualization of the presence of extrasynaptic sites on spines, dendrites and soma, and within intracellular compartments (Baude et al. 1995; He et al. 1998; Nusser et al. 1998; Petralia & Wenthold, 1999; Takumi et al. 1999b).

Considerable progress has been made recently in correlating dendritic spine morphology with the strength of the synapses formed on those spines. Differences in size of the spine head are correlated with differences in the size of the PSD, i.e. the smaller the spine head, the smaller the PSD. In contrast, larger mushroom spines have larger PSDs, which are often perforated (Harris & Stevens, 1989; Harris et al. 1992). The functional relevance of dendritic spine shape has been a source of much speculation and controversy. It has been previously suggested that spine shape influences the compartmentalization of electrical signals (Tsay & Yuste, 2004; Bloodgood et al. 2009), calcium dynamics (Sabatini et al. 2002; Holcman et al. 2004; Hayashi & Majewska, 2005) and protein synthesis (Steward & Falk, 1985; Steward & Schuman, 2001).

As changes in synaptic connectivity may permit the refinement of neural circuits and because the formation of new memories are thought to occur through activity-dependent re-wiring of synapses, there have been many investigations into the formation, shape and maintenance of dendritic spines. In this review, I discuss the roles of modulations of AMPA and NMDA receptors in dendritic spine formation, maintenance, motility and plasticity.

Glutamate receptors and dendritic spine development

Dendritic spines appear in the early stages of development shortly after dendritic processes are formed from neurons. Several lines of evidence suggest different ways of dendritic spine formation. During synapse development, pyramidal cell dendrites in the hippocampus extend numerous protrusions, known as filopodia. These filopodia are highly motile and can extend up to 10 μm in length. They can grow and retract within seconds to minutes, this motility allowing them to be well suited for exploring the neuropil to search for appropriate target synapses (Dailey & Smith, 1996; Shepherd, 1996; Ziv & Smith, 1996; Yuste & Bonhoeffer, 2004; Jontes & Smith, 2000; Portera-Cailliau & Yuste, 2001; Portera-Cailliau et al. 2003). The motility of filopodia is an actin-dependent process. There is disagreement in the field over whether filopodia have presynaptic contacts or not. Electron microscopy has revealed that some filopodia have no presynaptic contacts while others do (Fiala et al. 1998). It has been suggested that a filopodium can initiate contact with a growing axon in close proximity to form a synapse (Jontes & Smith, 2000; Yuste & Bonhoeffer, 2004). The filopodium then evolves directly into a dendritic spine or leads to the formation of a shaft synapse from which a spine arises at later stages of synaptogenesis (Fiala et al. 1998). Blockade of NMDA and AMPA receptors with bath applied antagonists induces a decrease in the density and turnover of dendritic filopodia. Local puffs of small amounts of glutamate close (100–200 μm) to dendritic filopodia have been reported to have different effects. In some cases, the motility of the filopodium was blocked by glutamate activation, whereas filopodia of more than 4 μm in length exhibited a small increase in length (Portera-Cailliau et al. 2003). Interestingly, when filopodia make contact to form glutamatergic synapses, the formation of stable contacts is insensitive to glutamate receptor antagonists (Lohmann & Bonhoeffer, 2008). Yet somehow dendritic filopodia do not make long-lasting stable contacts with inhibitory axons, suggesting that some signal is transmitted to the filopodia which is not activating glutamate receptors. It has recently been shown that calcium transients are the signal for selecting filopodia stability on glutamatergic synapses, thereby suggesting that calcium signalling regulates the stability of glutamatergic contacts (Lohmann & Bonhoeffer, 2008). For more details of the cellular and molecular mechanisms underlying formation of dendritic filopodia and transformation of filopodia to dendritic spines, see the review by Yoshihara and colleagues (2009).

Despite the evidence that dynamic filopodia make contact with their presynaptic partners and mature into dendritic spines, other modes of spinogenesis have been suggested. Electron microscopy studies during synaptogenesis have shown that the formation of asymmetric shaft synapses precedes the formation of dendritic spines (Fiala et al. 1998; Yuste & Bonhoeffer, 2004). In addition, dynamic imaging studies have revealed that spines can form directly from the dendritic shaft (Dailey & Smith, 1996), suggesting that presynaptic axons can somehow recognize shafts of dendrites and induce the postsynaptic cell to form a dendritic spine in close apposition to the axon terminal (Fiala et al. 1998; Yuste & Bonhoeffer, 2004). Recent studies have revealed the acquisition of PSD-95 in newly formed spines is delayed and significantly reduced by blockade of glutamate receptors, suggesting that synaptic activity plays a major role in PSD-95 expression (De Roo et al. 2008) and formation of functional synapses.

AMPA and NMDA receptors are colocalized at the postsynaptic membrane of most excitatory synapses (Kharazia & Weinberg, 1997; Nusser, 2000). Interestingly, the ratio of AMPA and NMDA receptors has been reported to change during development (Gomperts et al. 1998; Petralia et al. 1999; Liao et al. 1999, 2001; Pickard et al. 2000). Many forms of activity-dependent regulation of synapses, in vivo and in vitro, require NMDA receptor activation (Malenka & Nicoll, 1993; Huang & Pallas, 2001). In the early stages of postnatal cortex development, a large fraction of hippocampal synapses contain mainly NMDA receptors. As NMDA receptors do not produce substantial current flow at the resting membrane potential, these synapses can appear functionally or electrophysiologically ‘silent’ (Kerchner & Nicoll, 2008). The proportion of silent synapses is thought to be high in early postnatal life but gradually declines during development. Most mature synapses have a predominance of AMPA receptors. Silent synapses can accumulate AMPA receptors in an activity-dependent manner (Isaac et al. 1995; Liao et al. 1995, 1999; Durand et al. 1996; Petralia et al, 1999). However, other studies suggest that AMPA and NMDA receptors arrive at hippocampal synapses at approximately the same time (Friedman et al. 2000; Xiao et al. 2004; Hall & Ghosh, 2008; Zito et al. 2009). Although the presence of AMPA receptors during synapse development remains unresolved, the discrepancies may be due to different activity levels intrinsic to the synaptic networks examined. Synaptic maturation and induction of LTP, a widely studied cellular model of learning and memory, are accompanied by the appearance of functional AMPA receptors at previously silent synapses. The morphological correlates of silent synapses are as yet unknown. One can speculate that the spine head would be small in size as it is well documented that the bigger the spine head the more AMPA receptors are present. We have investigated the involvement of AMPA and NMDA receptors in the structural and functional development of CA1 pyramidal cells.

Chronic blockade of NMDA receptors for the first 2 weeks of postnatal development, a time point when more silent synapses could be present, had no effect on dendritic spine number or shape (Lüthi et al. 2001). We observed a marked increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and an increase in the dendritic tree arborization. Findings from this work suggested that NMDA receptor activation is not necessary for dendritic spine or synapse formation but is essential for limiting or pruning synaptic connections during network maturation. Another study using NMDA receptor antagonists also revealed that spines are still formed but the motility of the spines was increased (Alvarez et al. 2007). Interestingly, the authors found that the spines formed after RNA interference of the requisite NMDA receptor subunit NR1 were transient, as after a few weeks the spines and synapses disappeared but this was not observed in the spines formed after pharmacological blockade. Moreover, the role of NMDA receptors during synapse formation was further investigated recently when NMDA receptor protein expression was abolished in sparsely distributed cells in the hippocampus by introducing CRE recombinase to neurons in a floxed NR1 mouse. Genetic ablation of NMDA receptor function also induced an increase in the number of functional inputs (Adesnik et al. 2008). One can conclude from all these studies using multiple approaches that NMDA receptors are not essential for synapse development but are necessary and sufficient to limit synapse number. Is AMPA receptor activation necessary for synapse formation?

Recently, a single-cell genetic approach coupled with electrophysiology in hippocampal CA1 pyramidal neurons was used to investigate the role of AMPA receptors in synapse formation and the functional consequences of removing different AMPA receptor subunits on synaptic transmission during development. First, the majority of AMPA receptors expressed on CA1 pyramidal cells were composed of GluA1/A2 subunits, and the GluA2 subunit contained the edited site, strongly suggesting that the majority of AMPA receptors on CA1 cells are calcium impermeable. In cells lacking GluA1, -A2 and -A3, synapses were devoid of AMPA receptors, but synaptic NMDA receptors and dendritic spine morphology were unchanged (Lu et al. 2009). These findings suggest that spine formation during synaptogenesis is regulated by an intrinsic genetic programme and not activity. The initial formation of spines can occur without synaptic activity; in fact a study has shown that dendritic spines on cerebellar Purkinje cells can still form in the absence of axonal terminals (Cesa et al. 2005). One of the current main foci in spine plasticity is to determine to what extent spine formation and elimination are controlled by intrinsic genetic programmes.

An emerging area on the genetic control of spine plasticity is the many different gene products that are involved in actin polymerization and depolymerization in dendritic spine formation and elimination. Actin filaments form the main cytoskeleton of dendritic spines and underlie rapid motility of dendritic spines. The Rho family of GTPases, a subgroup of the Ras superfamily, is a key regulator of the actin cytoskeleton. The Rho GTPases RhoA, Rac, and Cdc42 all have been investigated with regard to their role in spine formation and shape determination (Newey et al. 2005). Rac and Rho have opposing effects on spine number. Constitutively active RhoA induces a decrease in spine length and number, whereas constitutive expression of an active Rac1 leads to the formation of many thin, small dendritic spines. The roles of some of the guanine nucleotide exchange factors (GEFs) or GTPases in activating proteins that regulate Rho family GTPases have recently been elucidated. One such example, the GEF kalirin-7, activates Rac1, as well as its downstream effector p21-activated kinase (PAK), a protein kinase. PAK phosphorylates and inactivates actin-depolymerizing factor/cofilin, which alters the morphology of the spine head (Xie et al. 2008).

Glutamate receptor involvement in spine stability and maintenance

As dendritic spines are the major sites of the postsynaptic component of excitatory synapses in the CNS, changes in spine shape or spine elimination would have an affect on brain microcircuitry and cognitive function. Therefore, it is necessary to determine factors involved in dendritic spine maintenance. Previously, we have investigated the influence of synaptically released glutamate on dendritic spine number and shape in mature hippocampi after synaptogenesis has occurred by comparing the affects of deafferentation, glutamate receptor antagonists, and blockers of glutamate release in mature hippocampal slice cultures (McKinney et al. 1999) (Fig. 2). We observed a significant decrease in spine density and length on CA1 cells after lesioning of Schaffer collaterals and after application of AMPA receptor antagonists or blockade of spontaneous glutamate release by the addition of botulinum toxin to unlesioned cultures. From these findings, we suggest that the lack of AMPA receptor activation following degeneration of presynaptic afferents initiates the process of spine retraction in postsynaptic CA1 pyramidal cells. Loss of spines and synapses induced by lesion or by botulinum toxin was prevented by simultaneous AMPA application. We conclude that synaptically released glutamate exerts a trophic effect on spines by acting at AMPA receptors, which is sufficient to maintain dendritic spines. Using ultrastructural methods, we have recently observed that synapses as well as spines were lost, concomitant with an increase in the number of asymmetric shaft synapses. Interestingly, we found that the mushroom shaped spines were unchanged. Furthermore, the synapses still remained plastic but the threshold of the dynamic range for plasticity was adjusted (McKinney et al. 1999; Mateos et al. 2007). More detailed analysis of the different spine shapes revealed that long thin spines were most affected by AMPA receptor blockade. It remains to be determined whether a particular shape of spine is more likely to convert to an asymmetric shaft synapse or lose its synaptic contact. Nonetheless, despite this loss of synapses and spines, the remaining synapses were still functional; there was no significant change in frequency of mEPSCs, indicating that there was a homeostatic rearrangement of the microcircuitry to preserve synaptic function.

Figure 2. Chronic blockade of AMPA receptors on mature dendritic spines results in synapse loss and an increase in excitatory shaft synapses.

Figure 2

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Illustration of 3D reconstruction from serial electron microscopy from control (left) and sister cultures chronically treated with an antagonist for AMPA receptors (right) (modified from Mateos et al. 2007). Scale bar, 0.5 μm.

Different spine type sensitivity to chronic AMPA receptor blockade is consistent with other properties described as spine-type dependent. Thin spines are considered to be more plastic structures and to represent less mature synapses (see Ziv & Smith, 1996; Fiala et al. 1998; Yuste & Bonhoeffer, 2001; Portera-Cailliau et al. 2003; Wallace & Bear, 2004). The functional relevance of dendritic spine shape has been a source of much speculation. A strong correlation between size of spine head and the strength of the synapse is most probably related to the higher level of AMPA receptors in larger spines. There is also evidence that the smaller or weaker spines preferentially undergo LTP, whereas the larger spines are more stable and show less plasticity (Matsuzaki et al. 2004). These observations have led to the idea that thin spines might be the ‘plastic’ spines and large mushroom spines the ‘memory’ spines (Kasai et al. 2003; Bourne & Harris, 2007).

In contrast, chronic blockade with NMDA receptor antagonists on mature dendritic spines results in no significant change in the density of dendritic spines but many long (2 μm) thin dendritic protrusions resembling filopodia are formed similar to the structures noted in immature hippocampus (McKinney et al. 1999). Interestingly, in vivo blockade of NMDA receptors (Woolley & McEwen, 1994) also has no affect on dendritic spine density but many long thin filopodia-like processes were also observed (Cooper & Smith, 1992; Papa et al. 1995; Fiala et al. 1998). Filopodia-like processes are thought to actively initiate synaptic contacts with axons in close proximity. Insufficient NMDA receptor activation appears to return the spines of CA1 pyramidal cells to an early development scenario whereby they actively search for presynaptic boutons with which to form synapses.

Spine motility

In the past 20 years it has been shown that dendritic spines are motile structures which are capable of undergoing significant changes in shape both in vitro and in vivo, ranging from seconds (Fischer et al. 1998; Dunaevsky et al. 1999; Korkotian & Segal, 2001) to tens of minutes or days (Engert & Bonhoeffer, 1999; Maletic-Savatic et al. 1999; Trachtenberg et al. 2002; Richards et al. 2005; Bhatt et al. 2009). These movements are known to occur through an actin-dependent process as motility can be halted by blockade of actin polymerization (Matus, 2000; Ethell & Pasquale, 2005; Tada & Sheng, 2006). Movements of the dendritic spines can occur without loss of their presynaptic contacts (Umeda et al. 2005). As spines contain postsynaptic elements of a synapse, their dynamics could influence synaptic efficacy which would be affected by changes in synaptic transmission. It has been shown in hippocampal cultures that spine dynamics are inhibited by activation of glutamatergic receptors, while antagonists to NMDA receptors have no effect on spine motility (Fischer et al. 2000). Interestingly, spine motility is not correlated with the developmental expression of AMPA and NMDA receptors or with the ability to flux calcium ions which would stabilize the cytoskeletal network. One can conclude that spine motility is affected by glutamate receptor activity but surprisingly not by glutamate receptor composition.

It is logical that spine motility plays a role in synapse formation in the developing nervous system but the function of the persistence of motility beyond development in mature spines in vivo and in vitro is less clear. One possible function would be the ability to rapidly change the biochemical compartmentalization allowing for the adjustment of signalling properties of the synapse. Alternatively, such morphing of the dendritic spine may be the consequence of postsynaptic membrane trafficking. Active exocytosis and endocytosis, which continually remodel the synaptic membrane, mediate receptor turnover and thereby synapse strength. We have previously investigated the diffusion of a membrane marker in dendritic spines using fluorescence recovery after photobleaching (FRAP), where a region is bleached and the recovery of the fluorescence in the bleached area is measured (Richards et al. 2004). We determined whether the FRAP kinetics were modified by spine motility and glutamate receptors. This work showed that a link between cell motility and glutamate receptor activation results in severing of these connections between the cytoskeleton and membrane (Fig. 3). This glutamatergic regulation of membrane dynamics is likely to have important implications for the clustering of postsynaptic receptors promoting or inhibiting exchange of extrasynaptic receptors bound within the PSD. Glutamate receptor activation with exogenous AMPA induced depolymerization of actin, preventing spine motility, which was accompanied by a decrease in the diffusion time of membrane-GFP (mGFP). Treatment with latrunculin A, an agent that prevents actin polymerization, also increased the rate of mGFP diffusion. These findings suggest that glutamate receptors regulate the mobility of substances in the inner leaflet of the plasma membrane through an action upon the actin cytoskeleton (Richards et al. 2004). We proposed that periods of synaptic inactivity lead to nucleation and branching adjacent to or at the plasma membrane, leading to an increase in spine motility. Synaptic activity, mimicked by the agonist AMPA, probably acting through intracellular calcium, reverses this process leading to a breakdown of branched actin filaments at the spine, making the spine more rounded and static. Regulation of spine/dendritic diffusion equilibration may have several functional consequences, as the susceptibility of individual synapses to plasticity induction may be influenced by the ability of signalling molecules and receptors to move in and out of the spine head.

Figure 3. Inverse correlation between spine motility and membrane trafficking.

Figure 3

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The more motile the dendritic spine the slower the diffusion co-efficient of membrane bound GFP after FRAP analysis (modified from Richards et al. 2004).

Mature spine remodelling

It has been speculated that memories that last for long periods of time, i.e. longer than hours or days, must be encoded in the form of a quasi-permanent morphological change in the activated synapse. Remarkable progress has been made in unravelling the physiology and molecular biology of learning and memory, but much less work has been performed in determining whether there is a morphological correlate of memory. The search for morphological plasticity has centred on the dendritic spines. Increase in the strength of the synaptic connection could be encoded structurally as (a) an increase in the number of contacts between two cells, (b) an increase in the size of the spine head to accommodate more glutamate receptors, or (c) a dilatation of the spine neck, so that currents generated in the spine head more readily depolarize the parent dendrite. In experimental paradigms using the cellular model of learning and memory, LTP, data indicate that all three changes accompany induction of LTP in brain slices or learning in living animals. Increase in the number of sites should be apparent as an increase in spine density and some (Moser et al. 1994; Geinisman, 2000), but not all (Sorra & Harris, 1998; Bagal et al. 2005), studies have supported this possibility. Induction of LTP using photoactivation of caged glutamate or tetanic synaptic stimulation, while simultaneously visualizing spines labelled with fluorescent markers, revealed a 50% increase in spine head volume within 1–5 min post-stimulation (Matsuzaki et al. 2004). Interestingly, the degree of spine head enlargement depended strongly on the initial naive spine size. Almost all spines showed a transient enlargement, but only small spines become persistently increased in volume after stimulation with caged glutamate. Like LTP, spine head enlargement requires activation of NMDA receptors and the intracellular kinase, CaMKII. These data suggest that the spine head must become bigger in order to accommodate newly inserted AMPA receptors, which are known to be recruited to the postsynaptic membrane with a concurrent increase in AMPA-mediated transmission after LTP induction. However, spine head growth may not be an obligatory concomitant of LTP, as it is not seen in all studies, despite equivalent LTP induction (Enoki et al. 2009).

Synapses can also undergo reduction of the strength of the synapse in the process known as long-term depression (LTD), which is induced with prolonged periods of stimulation of a moderate frequency. Morphological changes such as spine loss and decrease in size have been reported after LTD (Nagerl et al. 2004; Okamoto et al. 2004, Zhou et al. 2004). These changes are more pronounced in younger preparations. Increasing evidence suggests that inactivity extending for several days induces changes in the structure and function of hippocampal synapses. We have previously reported glutamate receptor-dependent extension of processes from large mushroom type dendritic spines, from transgenic mice expressing mGFP under the Thy1 promoter during episodes of reduced neuronal activity (Richards et al. 2005). We used live-cell imaging of mGFP-labelled CA1 pyramidal cells dendrites in organotypic slice cultures in vitro for 3–6 weeks. Blockade of action potential evoked release with tetrodotoxin (a Na+ channel blocker) resulted in an increase in the formation of large spinule-like projections or spine head protrusions (SHPs) from preexisting dendritic spine heads of mushroom shaped spines. Electron microscopy revealed that within 2 h of TTX application the original PSD remained and there was a PSD already in the SHPs apposed to a vesicle containing nerve terminal. This suggests that SHPs form new functional synapses. The formation of SHPs is blocked by AMPA/kainate receptor antagonists, which prevents spines from sensing glutamate via AMPA receptors, and also by AMPA itself, which stabilizes spines due to the depolymerization of actin. Spine head protrusions ‘reach out’ to contact nearby boutons and appear to form new synapses. This is further strengthened by the observation that exogenously locally applied glutamate puffs trigger the formation of SHPs. Spine head protrusions are occasionally observed in control hippocampi but are more prominent with reduced activity. From these findings we suggest that spines can compare their recent history with that of neighbouring synapses and modify local connectivity accordingly, allowing the network to maintain homeostasis (Richards et al. 2005).

Current investigations will determine whether these branched spines are forerunners to splitting of the presynaptic terminal. Why this phenomenon only occurs in a subset of mature large spines and how the SHPs determine the directionality to a presynaptic target where it makes a contact are as yet unknown. These observations strongly suggest that if a spine has not been recently activated by glutamate released by its presynaptic partner, it can respond to glutamate released by a neighbouring synapse. In contrast, if there is too much activity or release of glutamate, the dendritic spines can retract and lose their synaptic contacts. The findings from this work suggest that one of the physiological roles of spine motility is to allow spines to ‘compare’ their individual recent history with the level of activity of neighbouring synapses and modify hippocampal microcircuitry accordingly.

Outlook

Ever since dendritic spines were first described by Cajal over 100 years ago, they have been a major focus of studies in neuroscience. Recently, advances in imaging techniques and molecular markers have permitted the possibility of addressing many outstanding fundamental questions on neuronal circuitry in vitro and in vivo. Abnormalities in dendritic spine morphology and spine density are associated with a variety of psychiatric and neurological diseases. Interestingly, in virtually every disease in which cognitive performance is impaired, there is a dysgenesis of dendritic spines (Nimchinsky et al. 2002). For conditions such as epilepsy, Alzheimer's and ageing, it is not known whether spine abnormalities are a direct cause of synaptic dysfunction resulting in cognitive deficits or are secondary to some other event. Although still far from being complete, the molecular understanding and environmental effects of the pathogenetic process seem to be most advanced in some hereditary forms of mental retardation, such as fragile X syndrome, where proteins that regulate spine development and maintenance have been found to be affected. A greater understanding of the role that dendritic spines play in determining synaptic efficacy and the expression of synaptic plasticity will provide a better insight into the relationship between cognitive deficits and their morphological changes in spine shape and number in these various diseases.

Acknowledgments

I wish to thank David Verbich for critical review of the manuscript. I apologize to those whose work could not be cited due to space limitations. R.A.M. was supported by a Fonds de la Recherche en Santé Québec Senior Salary Bursary and the Hugh and Helene McPherson Memorial award. Work in the laboratory is supported by grants from Canadian Institute of Health Research and National Sciences Engineering Research Council of Canada.

References

  1. Adesnik H, Li G, During MJ, Pleasure SJ, Nicoll RA. NMDA receptors inhibit synapse unsilencing during brain development. Proc Natl Acad Sci U S A. 2008;105:5597–5602. doi: 10.1073/pnas.0800946105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alvarez VA, Ridenour DA, Sabatini BL. Distinct structural and iontotropic roles of NMDA receptors in controlling spine and synapse stability. J Neurosci. 2007;27:7365–7376. doi: 10.1523/JNEUROSCI.0956-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bagal AA, Kao JPY, Tang CM, Thompson SM. Long-term potentiation of exogenous glutamate responses at a single dendritic spine. Proc Natl Acad Sci U S A. 2005;102:14434–14439. doi: 10.1073/pnas.0501956102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baude A, Nusser Z, Molnar E, McIlhinney RA, Somogyi P. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus. Neuroscience. 1995;69:1031–1055. doi: 10.1016/0306-4522(95)00350-r. [DOI] [PubMed] [Google Scholar]
  5. Bhatt DH, Zhang S, Gan WB. Dendritic spine dynamics. Annu Rev Physiol. 2009;71:261–282. doi: 10.1146/annurev.physiol.010908.163140. [DOI] [PubMed] [Google Scholar]
  6. Bloodgood BL, Gissel AJ, Sabatini BL. Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines. PLOS Biol. 2009;7:1–10. doi: 10.1371/journal.pbio.1000190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bourne JN, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381–386. doi: 10.1016/j.conb.2007.04.009. [DOI] [PubMed] [Google Scholar]
  8. Bourne JN, Harris KM. Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci. 2008;31:47–67. doi: 10.1146/annurev.neuro.31.060407.125646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cesa R, Morando L, Strata P. Purkinje cell spinogenesis in vivo change during maturation. J Neurosci. 2005;19:4472–4483. [Google Scholar]
  10. Cooper MW, Smith SJ. A real-time analysis of growth cone-target cell interactions during the formation of stable contacts between hippocampal neurons in culture. J Neurobiol. 1992;23:814–828. doi: 10.1002/neu.480230704. [DOI] [PubMed] [Google Scholar]
  11. Dailey ME, Smith SJ. The dynamics of dendritic structure in developing hippocampal slices. J Neurosci. 1996;16:2983–2994. doi: 10.1523/JNEUROSCI.16-09-02983.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. De Roo M, Klauder P, Muller D. LTP promotes a selective long-term stabilization and clustering of dendritic spines. PLOS Biol. 2008;6:e219. doi: 10.1371/journal.pbio.0060219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A. 1999;96:13438–13443. doi: 10.1073/pnas.96.23.13438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Durand GM, Kovalchuk Y, Konnerth A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature. 1996;381:71–75. doi: 10.1038/381071a0. [DOI] [PubMed] [Google Scholar]
  15. Ethell IM, Pasquale EB. Molecular mechanisms of dendritic spine development and remodelling. Prog Neurobiol. 2005;75:161–205. doi: 10.1016/j.pneurobio.2005.02.003. [DOI] [PubMed] [Google Scholar]
  16. Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999;399:66–70. doi: 10.1038/19978. [DOI] [PubMed] [Google Scholar]
  17. Enoki R, Hu YL, Hamilton DA, Fine A. Expression of long-term plasticity at individual synapses in hippocampus is graded, bidirectional and mainly presynaptic: optical quantal analysis. Neuron. 2009;62:242–253. doi: 10.1016/j.neuron.2009.02.026. [DOI] [PubMed] [Google Scholar]
  18. Fiala JC, Feinberg M, Popov V, Harris KM. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci. 1998;18:8900–8911. doi: 10.1523/JNEUROSCI.18-21-08900.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fischer M, Kaech S, Knutti D, Matus A. Rapid actin-based plasticity in dendritic spines. Neuron. 1998;20:847–854. doi: 10.1016/s0896-6273(00)80467-5. [DOI] [PubMed] [Google Scholar]
  20. Fischer M, Kaech S, Wagner U, Brinkhaus H, Matus A. Glutamate receptors regulate actin-based plasticity in dendritic spines. Nat Neurosci. 2000;3:887–894. doi: 10.1038/78791. [DOI] [PubMed] [Google Scholar]
  21. Friedman HV, Bresler T, Garner CC, Ziv NE. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron. 2000;27:57–69. doi: 10.1016/s0896-6273(00)00009-x. [DOI] [PubMed] [Google Scholar]
  22. Geinisman Y. Structural synaptic modifications associated with hippocampal LTP and behavioural learning. Cereb Cortex. 2000;10:952–962. doi: 10.1093/cercor/10.10.952. [DOI] [PubMed] [Google Scholar]
  23. Gomperts SN, Rao A, Craig AM, Malenka RC, Nicoll RA. Postsynaptically silent synapses in single neuron cultures. Neuron. 1998;21:1443–1451. doi: 10.1016/s0896-6273(00)80662-5. [DOI] [PubMed] [Google Scholar]
  24. Hall BJ, Ghosh A. Regulation of AMPA receptor recruitment at developing synapses. Trends Neurosci. 2008;31:82–89. doi: 10.1016/j.tins.2007.11.010. [DOI] [PubMed] [Google Scholar]
  25. Harris KM, Stevens JK. Dendritic spines of CA1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristic. J Neurosci. 1989;9:2982–2997. doi: 10.1523/JNEUROSCI.09-08-02982.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Harris KM, Jensen FE, Tsoa 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. doi: 10.1523/JNEUROSCI.12-07-02685.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hayashi Y, Majewska AK. Dendritic spine geometry: functional implication and regulation. Neuron. 2005;46:529–532. doi: 10.1016/j.neuron.2005.05.006. [DOI] [PubMed] [Google Scholar]
  28. He Y, Janssen WG, Vissavajjhala P, Morrison JH. Synaptic distribution of GluR2 in hippocampal GABAergic interneurons and pyramidal cells: a double-label immunogold analysis. Exp Neurol. 1998;150:1–13. doi: 10.1006/exnr.1997.6720. [DOI] [PubMed] [Google Scholar]
  29. Holcman D, Schuss Z, Korkotian E. Calcium dynamics in dendritic spines and spine motility. Biophys J. 2004;87:81–91. doi: 10.1529/biophysj.103.035972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Huang L, Pallas SL. NMDA antagonists in the superior colliculus prevent developmental plasticity but not visual transmission or map compression. J Neurophysiol. 2001;86:1179–1194. doi: 10.1152/jn.2001.86.3.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Isaac JT, Nicoll RA, Malenka RC. Evidence for silent synapses: implications for the expression of LTP. Neuron. 1995;15:427–434. doi: 10.1016/0896-6273(95)90046-2. [DOI] [PubMed] [Google Scholar]
  32. Jones EG, Powell TP. Morphological variation in the dendritic spines of the neocortex. J Cell Sci. 1969;5:509–529. doi: 10.1242/jcs.5.2.509. [DOI] [PubMed] [Google Scholar]
  33. Jontes JD, Smith SJ. Filopodia, spines and the generation of synaptic diversity. Neuron. 2000;27:11–14. doi: 10.1016/s0896-6273(00)00003-9. [DOI] [PubMed] [Google Scholar]
  34. Kasai H, Matsuzaki M, Noguchi J, Yasumastu N, Nakahara H. Structure-stability-function relationships of dendritic spines. Trends Neurosci. 2003;26:360–368. doi: 10.1016/S0166-2236(03)00162-0. [DOI] [PubMed] [Google Scholar]
  35. Kerchner GA, Nicoll RA. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci. 2008;9:813–825. doi: 10.1038/nrn2501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kharazia VN, Weinberg RJ. Tangential synaptic distribution of NMDA and AMPA receptors in rat neocortex. Neurosci Lett. 1997;238:41–44. doi: 10.1016/s0304-3940(97)00846-x. [DOI] [PubMed] [Google Scholar]
  37. Kharazia VN, Phend KD, Rustioni A, Weinberg RJ. EM co-localization of AMPA and NMDA receptor subunits at synapses in rat cerebral cortex. Neurosci Lett. 1996;210:37–40. doi: 10.1016/0304-3940(96)12658-6. [DOI] [PubMed] [Google Scholar]
  38. Korkotian E, Segal M. Regulation of dendritic spine motility in cultured hippocampal neurons. J Neurosci. 2001;21:6115–6124. doi: 10.1523/JNEUROSCI.21-16-06115.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Liao D, Hessler NA, Malinow R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature. 1995;375:400–404. doi: 10.1038/375400a0. [DOI] [PubMed] [Google Scholar]
  40. Liao D, Zhang X, O’Brien R, Ehlers MD, Huganir RL. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nat Neurosci. 1999;2:37–43. doi: 10.1038/4540. [DOI] [PubMed] [Google Scholar]
  41. Liao D, Scannevin RH, Huganir R. Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J Neurosci. 2001;21:6008–6017. doi: 10.1523/JNEUROSCI.21-16-06008.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Lohmann C, Bonhoeffer T. A role of calcium signalling in rapid synaptic partner selection by dendritic filopodia. Neuron. 2008;59:253–260. doi: 10.1016/j.neuron.2008.05.025. [DOI] [PubMed] [Google Scholar]
  43. Lu W, Shi Y, Jackson AC, Bjorgan K, During MJ, Sprengel R, Seeburg PH, Nicoll RA. Subunit composition of synaptic AMPA receptors revealed by a single cell genetic approach. Neuron. 2009;62:254–268. doi: 10.1016/j.neuron.2009.02.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Lüthi A, Schwyzer L, Mateos JM, Gähwiler BH, McKinney RA. NMDA receptor activation limits the number of synaptic connections during hippocampal development. Nat Neurosci. 2001;11:1102–1027. doi: 10.1038/nn744. [DOI] [PubMed] [Google Scholar]
  45. Malenka RC, Nicoll RA. NMDA-receptor dependent synaptic plasticity: multiple forms and mechanism. Trends Neurosci. 1993;16:521–527. doi: 10.1016/0166-2236(93)90197-t. [DOI] [PubMed] [Google Scholar]
  46. Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science. 1999;283:1923–1927. doi: 10.1126/science.283.5409.1923. [DOI] [PubMed] [Google Scholar]
  47. Masugi-Tokita M, Tarusawa E, Watanabe M, Molnar E, Fujimoto K, Shigemoto R. Number and density of AMPA receptors in individual synapses in the rat cerebellum as revealed by SDS-digested freeze-fracture replica labelling. J Neurosci. 2007;27:2135–2144. doi: 10.1523/JNEUROSCI.2861-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Mateos JM, Lüthi A, Savic N, Sterli B, Streit P, Gähwiler BH, McKinney RA. Synaptic modifications at the CA3–CA1 synapse after chronic AMPA receptor blockade in rat hippocampal slices. J Physiol. 2007;581:129–138. doi: 10.1113/jphysiol.2006.120550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Matus A. Actin-based plasticity in dendritic spines. Science. 2000;290:754–758. doi: 10.1126/science.290.5492.754. [DOI] [PubMed] [Google Scholar]
  51. McKinney RA, Capogna M, Dürr R, Gähwiler BH, Thompson SM. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat Neurosci. 1999;2:44–49. doi: 10.1038/4548. [DOI] [PubMed] [Google Scholar]
  52. Morris RG. Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. Eur J Neurosci. 2006;23:2829–2846. doi: 10.1111/j.1460-9568.2006.04888.x. [DOI] [PubMed] [Google Scholar]
  53. Moser MB, Trommald M, Andersen P. An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci U S A. 1994;91:1263–12675. doi: 10.1073/pnas.91.26.12673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Nagerl UV, Eberhorn N, Cambridge SB, Bonhoeffer T. Bi-directional activity-dependent morphological plasticity in hippocampal neurons. Neuron. 2004;44:759–767. doi: 10.1016/j.neuron.2004.11.016. [DOI] [PubMed] [Google Scholar]
  55. Newey SE, Velamoor V, Govek EE, Van Aelst L. Rho GTPases, dendritic structure, and mental retardation. J Neurobiol. 2005;64:58–74. doi: 10.1002/neu.20153. [DOI] [PubMed] [Google Scholar]
  56. Newpher TM, Ehlers MD. Spine microdomains for postsynaptic signalling and plasticity. Trends Cell Biol. 2009;19:218–227. doi: 10.1016/j.tcb.2009.02.004. [DOI] [PubMed] [Google Scholar]
  57. Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol. 2002;64:313–353. doi: 10.1146/annurev.physiol.64.081501.160008. [DOI] [PubMed] [Google Scholar]
  58. 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;21:545–549. doi: 10.1016/s0896-6273(00)80565-6. [DOI] [PubMed] [Google Scholar]
  59. Nusser Z. AMPA and NMDA receptors: similarities and differences in their synaptic distribution. Curr Opin Neurobiol. 2000;10:337–341. doi: 10.1016/s0959-4388(00)00086-6. [DOI] [PubMed] [Google Scholar]
  60. Okabe S. Molecular anatomy of the postsynaptic density. Mol Cell Neurosci. 2007;34:503–518. doi: 10.1016/j.mcn.2007.01.006. [DOI] [PubMed] [Google Scholar]
  61. Okamoto K, Nagai T, Miyawaki A, Hayashi Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci. 2004;7:1104–1112. doi: 10.1038/nn1311. [DOI] [PubMed] [Google Scholar]
  62. Papa M, Bundman MC, Greenberger V, Segal M. Development and morphology of dendritic spines in primary cultures of hippocampal neurons. J Neurosci. 1995;15:1–11. doi: 10.1523/JNEUROSCI.15-01-00001.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006;313:1141–1144. doi: 10.1126/science.1128657. [DOI] [PubMed] [Google Scholar]
  64. Perez-Otano I, Lujan R, Tavalin SJ, Plomann M, Modregger J, Liu XB, Jones EG, Heinemann SF, Lo DC, Ehlers MD. Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nat Neurosci. 2006;9:611–621. doi: 10.1038/nn1680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Peters A, Kaiserman-Abramof IR. The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am J Anat. 1970;127:321–355. doi: 10.1002/aja.1001270402. [DOI] [PubMed] [Google Scholar]
  66. Petralia RS, Wenthold RJ. Immunocytochemistry of NMDA receptors. Methods Mol Biol. 1999;128:73–92. doi: 10.1385/1-59259-683-5:73. [DOI] [PubMed] [Google Scholar]
  67. Petralia RS, Esteban JA, Wang YX, Partridge JC, 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. doi: 10.1038/4532. [DOI] [PubMed] [Google Scholar]
  68. Pickard L, Noel J, Heneley JM, Collinridge GL, Molnar E. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J Neurosci. 2000;20:7922–7931. doi: 10.1523/JNEUROSCI.20-21-07922.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Portera-Cailliau C, Yuste R. On the function of dendritic filopodia. Rev Neurol. 2001;33:1158–1166. [PubMed] [Google Scholar]
  70. Portera-Cailliau C, Pan DT, Yuste R. Activity-regulated dynamic behaviour of early dendritic protrusions: evidence for different types of dendritic filopodia. J Neurosci. 2003;23:7129–7143. doi: 10.1523/JNEUROSCI.23-18-07129.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Richards DA, de Paola V, Caroni P, Gähwiler BH, McKinney RA. AMPA-receptor activation regulates the diffusion of a membrane marker in parallel with dendritic spine motility in the mouse hippocampus. J Physiol. 2004;558:503–512. doi: 10.1113/jphysiol.2004.062091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Richards DA, Mateos JM, Hugel S, de Paola V, Caroni P, Gähwiler BH, McKinney RA. Glutamate induces the rapid formation of spine head protrusions in hippocampal slice cultures. Proc Natl Acad Sci U S A. 2005;102:6166–6171. doi: 10.1073/pnas.0501881102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Rumpel S, LeDoux J, Zador A, Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning. Science. 2005;308:83–88. doi: 10.1126/science.1103944. [DOI] [PubMed] [Google Scholar]
  74. Sabatini BL, Oertner TG, Svoboda K. The life cycle of calcium ions in dendritic spines. Neuron. 2002;33:439–452. doi: 10.1016/s0896-6273(02)00573-1. [DOI] [PubMed] [Google Scholar]
  75. Sheng M, Hoogenraad CC. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu Rev Biochem. 2007;76:823–847. doi: 10.1146/annurev.biochem.76.060805.160029. [DOI] [PubMed] [Google Scholar]
  76. Shepherd GM. The dendritic spine: a multifunctional integrative unit. J Neurophysiol. 1996;75:2197–2210. doi: 10.1152/jn.1996.75.6.2197. [DOI] [PubMed] [Google Scholar]
  77. Sorra KE, Harris KM. Stability in synapse number and size at 2 hr after long-term potentiation in hippocampal area CA1. J Neurosci. 1998;18:658–671. doi: 10.1523/JNEUROSCI.18-02-00658.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Steward O, Schuman EM. Protein synthesis at synaptic sites on dendrites. Annu Rev Neurosci. 2001;24:299–325. doi: 10.1146/annurev.neuro.24.1.299. [DOI] [PubMed] [Google Scholar]
  79. Steward O, Falk PM. Polyribosomes under developing spine synapses: growth specializations of dendrites at sites of synaptogenesis. J Neurosci Res. 1985;13:75–88. doi: 10.1002/jnr.490130106. [DOI] [PubMed] [Google Scholar]
  80. Tada T, Sheng M. Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol. 2006;16:95–101. doi: 10.1016/j.conb.2005.12.001. [DOI] [PubMed] [Google Scholar]
  81. 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. 1999a;2:618–624. doi: 10.1038/10172. [DOI] [PubMed] [Google Scholar]
  82. Takumi Y, Matsubara A, Rinvik E, Ottersen OP. The arrangement of glutamate receptors in excitatory synapses. Ann N Y Acad Sci. 1999b;868:474–482. doi: 10.1111/j.1749-6632.1999.tb11316.x. [DOI] [PubMed] [Google Scholar]
  83. Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature. 2002;420:788–794. doi: 10.1038/nature01273. [DOI] [PubMed] [Google Scholar]
  84. Tsay D, Yuste R. On the electrical function of dendritic spines. Trends Neurosci. 2004;27:77–83. doi: 10.1016/j.tins.2003.11.008. [DOI] [PubMed] [Google Scholar]
  85. Umeda T, Ebihara T, Okabe S. Simultaneous observation of stably associated presynaptic varicosities and postsynaptic spines: morphological alterations of CA3-CA1 synapses in hippocampal slice cultures. Mol Cell Neurosci. 2005;28:264–274. doi: 10.1016/j.mcn.2004.09.010. [DOI] [PubMed] [Google Scholar]
  86. Wallace W, Bear MF. A morphological correlate of synaptic scaling in visual cortex. J Neurosci. 2004;24:6928–6938. doi: 10.1523/JNEUROSCI.1110-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science. 2006;313:1093–1097. doi: 10.1126/science.1128134. [DOI] [PubMed] [Google Scholar]
  88. Woolley CS, McEwen BS. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci. 1994;14:7680–7687. doi: 10.1523/JNEUROSCI.14-12-07680.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Xiao MY, Wasling P, Hanse E, Gustafsson B. Creation of AMPA-silent synapses in the neonatal hippocampus. Nat Neurosci. 2004;7:236–243. doi: 10.1038/nn1196. [DOI] [PubMed] [Google Scholar]
  90. Xie Z, Photowala H, Cahill ME, Srivastava DP, Woolfrey KM, Shum CY, Huganir RL, Penzes P. Coordination of synaptic adhesion with dendritic spine remodelling by AF-6 and kalirin-7. J Neurosci. 2008;28:6079–6091. doi: 10.1523/JNEUROSCI.1170-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Yoshihara Y, De Roo M, Muller D. Dendritic spine formation and stabilization. Curr Opin Neurobiol. 2009;19:146–153. doi: 10.1016/j.conb.2009.05.013. [DOI] [PubMed] [Google Scholar]
  92. Yuste R, Bonhoeffer T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci. 2001;24:1071–1089. doi: 10.1146/annurev.neuro.24.1.1071. [DOI] [PubMed] [Google Scholar]
  93. Yuste R, Bonhoeffer T. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat Rev Neurosci. 2004;5:23–34. doi: 10.1038/nrn1300. [DOI] [PubMed] [Google Scholar]
  94. Zhou Q, Homma KJ, Poo MM. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron. 2004;44:749–757. doi: 10.1016/j.neuron.2004.11.011. [DOI] [PubMed] [Google Scholar]
  95. Zito K, Scheuss V, Knott G, Hill T, Svoboda K. Rapid functional maturation of nascent dendritic spines. Neuron. 2009;61:247–248. doi: 10.1016/j.neuron.2008.10.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Ziv NE, Smith SJ. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron. 1996;17:91–102. doi: 10.1016/s0896-6273(00)80283-4. [DOI] [PubMed] [Google Scholar]

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