The molecular cascade of events associated with hippocampal processing of information for long-term storage is a time-limited event. Learning sets in motion neural processes that continue to evolve after training, a phenomenon known as consolidation. The consolidation process has been proposed to involve the translation of neural activity into enduring synaptic change by a cascade of sequential molecular steps involving gene induction, increased protein synthesis and synaptic growth mediated, in part, by cell recognition systems. However, evidence for dendritic remodelling being a mechanism of memory consolidation is still in its infancy. There is no clear consensus as to whether spine or synapse frequency change accompanies memory formation. This may arise from a failure to consider temporal change in synaptic dynamics during information processing. By contrast, there is significant evidence that the temporal orchestration of cell adhesion molecule function is an integral process for memory consolidation. An attractive possibility is that transmembrane cell adhesion molecule expression is modulated in an activity-dependent manner that permits rapid alteration in synapse structure and/or efficacy. Evidence exists to correlate cell adhesion molecule function with spine and synapse formation following learning but also for their increased synaptic expression in the absence of dendritic remodelling. There appears to be a need to correlate the temporal dynamics of cell adhesion molecule function to synapse structure if a morphological correlate of learning is to be established.

Introduction

An important problem in the neurobiology of memory is whether cellular mechanisms of learning and memory include the formation of new synapses or the remodelling of existing ones. To elucidate this problem, numerous studies have examined alterations in the number and structure of hippocampal dendritic spines and synapses (see Geinisman et al in this book). This brain region, along with associated cortical structures in the temporal lobe, has been implicated in holding and processing information destined for consolidation as long term memory within the neocortex.²Moreover, this consolidation process has been demonstrated to involve a molecular cascade of events within the medial temporal lobe in which enhanced neural activity activates gene transcription, protein synthesis and synaptic reorganisation.^5,37,70,72 Activity-dependent synapse selection is attractive in its simplicity and most likely will provide a basis to understand neuroplastic events subservient to behavioural adaptation in the adult animal.

Most excitatory synapses in the adult brain are located on the bulbous heads of dendritic spines,⁴⁵ where they occur in vast numbers, estimated to be in the order of 10 ¹⁴ for the human cerebral cortex.¹²¹ Dendritic filopodia are initially involved in the generation of shaft synapses, which later develop into spines.²⁸ This distinctive structure of dendritic spines is specialized by underlying microfilaments composed of actin that contrasts with the cytoplasmic microtubules that are dominant in the dendritic shaft.⁶⁸ The actin microfilaments are in close association with the postsynaptic density, a membrane specialization thought to be important for the clustering of postsynaptic receptors and ion channels and for the assembly of the postsynaptic signalling machinery.⁴²

Cell adhesion molecule-regulated cell-cell recognition and/or signal transduction events play an integral role in dendritic spine development and synapse elaboration.⁹ Cell-cell adhesion across the synaptic cleft is thought to hold the presynaptic active zone and the postsynaptic density in close register.³⁶ As yet, there is no clear consensus on the role of cell recognition systems in dendritic growth and synapse restructuring. Such molecules may function to promote dendritic growth and synapse formation and provide mechanisms that restrict elaboration of the dendritic arbor.¹⁵ Moreover, in the adult hippocampus, region-specific cell genesis has been suggested to contribute to the fine-tuning of the neural structure throughout life by invoking a developmental replay of cell-cell recognition events.⁵⁵

The challenge ahead lies in identifying the network of molecular interactions, including cell adhesion molecules (CAMs), that together produce the activity-induced morphological change, such as dendrite and synapse formation, as the greatest pitfall in research on activity-related plasticity is to overstate the relevance of single identified regulators.

Is Net Synapse Formation a Correlate of Learning?

Do Cell Adhesion Molecules Have a Role in Learning?

CAM Structure and Function

The spine surface exhibits an array of proteins many of which span the membrane thereby permitting bidirectional communication.¹³⁴ These proteins include ligand- and second messenger-gated ion channels, G-protein-coupled receptors and cell adhesion molecules that coexist in an organized but dynamic array in the postsynaptic density. Spectrin and spectrin-like proteins link these proteins to actin filaments that mingle with larger intermediate filaments in the spine head.

Analogous to the postsynaptic density, the presynaptic cytomatrix is organized into active zones that determine sites of synaptic vesicle fusion and recycling. These active zones are likely to spatially restrict proteins involved in vesicle docking and fusion, such as the SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein) receptor complex and synaptotagamin. In addition, the active zone includes cytoskeletal proteins, such as members of the membrane-associated guanylate kinase (MAGUK) superfamily, as well as other multidomain proteins that are tightly associated with synaptic junctions. These are thought to function as adaptor proteins involved in localizing and assembling pre- and postsynaptic signalling complexes that also include cell adhesion molecules.³⁶

The cell adhesion molecules (CAMs) localised to the synaptic complex include representatives from the cadherin, immunoglobulin and integrin superfamilies and, in addition, the neurexins and neuroligands.⁹ The cadherins mediate Ca2+-dependent cell-cell adhesion that is mainly trans homophilic. They have a single pass membrane domain that interacts with the actin cytoskeleton via a group of proteins termed the catenins. The integrins are formed from two non-covalently linked heterodimeric proteins that have single pass membrane domains that can link to actin by a variety of adaptor proteins, such as talin or vinculin. The extracellular domains of the integrins form a ligand binding site that requires divalent cations and interacts with defined matrix protein sequences (such as _Arg-Gly-Asp-).⁴ The immunoglobulin superfamily is characterized by the presence of Ig-like domains and fibronectin repeats in their extracellular domains.

These adhesion molecules can interact in a hetero- or homophilic manner between cells (trans interactions) or in the same plane of the membrane (cis interactions) (Fig. 1). Many CAMs have single pass membrane domains, some of which interact with actin, or attach to the cell surface via a glycosylphosphatidylinositol linkage. The neurexins and neuroligands are located to the pre- and postsynaptic membranes, respectively, and mediate Ca2+-dependent cell-cell adhesion through their extracellular N-terminal domains.

Figure 1

Proposed modes of CAM-CAM interactions and cell signalling. The blue and white bars represent individual CAMs that traverse the plasma membrane (black line). Trans homo- and heterophilic binding occurs between two apposing plasma membranes. By contrast, (more...)

Unfortunately, the precise mechanism(s) of CAM signalling still remain to be resolved. ^{18,41,56,67,131}

Do Cell Adhesion Molecules Have a Temporal Role in Learning?

The molecular cascade of events associated with hippocampal processing of information for long-term storage is a time-limited event (Fig. 2).^58,72,135 Learning sets in motion neural processes that continue to evolve after training, a phenomenon known as consolidation. The consolidation process has been proposed to involve the translation of neural activity into enduring synaptic change by a cascade of sequential molecular steps involving gene induction, increased protein synthesis and synaptic growth mediated, in part, by cell recognition systems.⁶ As time passes, a more permanent memory develops which is independent of the hippocampal formation and most likely located in the neocortex. Such studies have contributed to a model of memory consolidation in which the medial temporal lobe memory system serves as a temporary reservoir prior to the eventual storage of long term memory within the cortex.²

Figure 2

Temporal involvement of hippocampal formation in memory consolidation. This figure illustrates memory recall in rodents, primates and humans with hippocampal lesions at increasing times following paradigm acquisition. The data is expressed as percent (more...)

At least two temporally and mechanistically distinct processes contribute to activity-dependent synaptic plasticity, which lasts from tens of minutes to hours or more. After its induction, LTP passes through a 30-60min period during which unknown chemistries make it progressively less vulnerable to disruption or reversal. For example, hypoxia of duration just sufficient to transiently block synaptic responses completely eliminates LTP when applied within the first minutes after induction but is without effect 30min later.³ Also, LTP reversal is readily obtained with theta pattern stimulation when applied within the first minutes and becomes progressively less effective over 30min post-induction.¹¹¹

Little is known about the neurochemical events responsible for consolidation. Protein and mRNA synthesis inhibitors are reported to dissipate LTP beginning several hours after induction.⁸⁰ Whether this reflects a need for newly synthesised molecules in order for potentiation to enter a late stage, as opposed to sustaining already established LTP, is an unresolved issue. In any event, the effects obtained with protein synthesis inhibitors develop too slowly to be part of the stabilisation process that begins within the first minute after induction.

Certain classes of adhesion receptors may be better candidates. Several of the more than 20 known integrins are expressed by hippocampal neurons and at least some of these are concentrated in the synapses⁹¹ and many of these have been implicated in the stabilization of LTP. For example, function blocking antibodies to the a5 or _ integrin subunits have no effect on initial potentiation but significantly reduce it 45min later whereas antibodies to the a(v) or a2 integrin subunits are without effect.¹⁴ Moreover, function blocking with antibodies to the a3 integrin subunit stabilize slow decay of LTP.⁶² Members of the immunoglobulin superfamily also appear to be involved in the maintenance of LTP as judged by the increased expression of neuroplastin-65 and NCAM180 in the late phase following the induction of LTP.^104,109

There is also evidence for the temporal involvement of CAMs in the consolidation processes that follow behavioural adaptation. For example, intraventricular administration of anti-L1 effectively blocks the acquisition of avoidance conditioning when administered just prior to training and, specifically, in the 5-8h and 15-18h post-training periods.^103,123 Similarly, anti-NCAM has been found to induce amnesia of avoidance conditioning and odour discrimination paradigms when administered in the 6-8h post-training period.^21,96,102 More recently, NCAM has been demonstrated to play a role in the acquisition of passive avoidance learning. Intraventricular infusions of a synthetic peptide ligand of NCAM (C3) strongly inhibited recall of a passive avoidance response in adult rats when given during training or in the 6-8 hours post-training period.³⁰ This peptide has an affinity for the IgI domain and the capability of disrupting NCAM-mediated neurite outgrowth in vitro.⁹³

This unique amnesic action of the C3 peptide has also been related to disrupted NCAM internalization immediately following training. In the 3-4h period following training NCAM180, the synapse-associated isoform, becomes down-regulated in the dentate gyrus of the hippocampal formation. This effect is mediated by ubiquitination and prevented by C3 peptide administration during training. Thus, these findings indicate NCAM to be involved in the acquisition and in the later 6-8h post-training consolidation of a passive avoidance response in the rat. Moreover, this study provided the first in vivo evidence for CAM internalization in learning, an observation presaged by studies on ApCAM, the Aplysia NCAM homologue, that has been demonstrated to rapidly down-regulate and become internalized in an in vitro model of long-term sensitization of the gill and siphon-withdrawal reflex.^7,69 Internalization of CAMs may be a general mechanism for the dynamic modulation of synaptic plasticity during memory consolidation. Both NCAM and L1 are also endocytosed by clathrin-dependent pathways^54,73 and growth cone elaboration has been associated with endocytosis-dependent recycling of L1.⁵³

Can Cell Adhesion Molecules Reveal Memory Pathway?

Studies of memory-related modifications in the mammalian brain are severely restricted by the difficulty of identifying the network in which specific memory-induced changes occur, and by the prospect that these cellular changes are too subtle to be distinguished from the background of previously acquired memories. This conundrum has, in part, been overcome by the development of a unique probe to a CAM glycosylation variant.

NCAM Polysialylation

A significant post-translational modification of NCAM involves the attachment of large homopolymers of a2,8 polysialic acid (PSA), a modification that is specific to NCAM in the mammalian brain (Fig. 3).^95,98 This post-translational modification of NCAM with PSA is believed to modulate NCAM-mediated homophilic adhesion and/or signal transduction events by virtue of its extensive negative charge .^47,131,133 By attenuating adhesion forces and modulating overall cell surface interactions, NCAM PSA has the potential to orchestrate dynamic changes in the shape and movement of cells, as well as their processes.^57,94

Figure 3

Structure and mode of NCAM-NCAM interactions.. The upper panel illustrates the basic structural features of NCAM. The three major splice variants—NCAM 180, NCAM 140 and NCAM 120—associate with the membrane by a single transmembrane domain (more...)

The development of a monoclonal antibody to extended chains of PSA found on meningococcus group B polysaccharides⁹⁵ provided an unparalleled immunohistochemical tool for mapping PSA expression in the mammalian central nervous system. Moreover, a bacteriophage-derived endoneuraminidase (endo-N), that cleaves polysialosyl units associated with the K1 capsular antigen of certain Escherichia coli strains, provided the ideal control for these immunohistochemical procedures.^29,128 Both anti-PSA and endo-N require a minimum recognition size of at least 10-12 residues^46,71and, as a consequence, only NCAM with extended chains of polysialic acid is recognised.

Using these tools the distribution of NCAM PSA in the adult brain has been mapped and found to be associated primarily with those brain regions that undergo structural reorganization and synaptic plasticity, such as the olfactory bulb, hypothalamus and hippocampal formation and its associated structures in the medial temporal lobe.^{12,31,32,74,81,83,106} This convergent set of data has been used to suggest that NCAM PSA supports structural plasticity in adult nervous system.⁵⁷ NCAM PSA has also been implicated in activity-dependent synaptic remodelling. The hypothalmo-neurohypophysial system expresses high levels of NCAM PSA throughout life and undergoes extensive morphological synaptic plasticity in response to physiological stimuli that is dependent on the surface expression of polysialylated NCAM.^48,82 For example, microinjection of endo-N blocks cell surface expression of NCAM PSA and the synapse increase that occurs in response to lactation or osmotic stimulation.¹²²

Consistent with this view is that removal of PSA with endoneuraminidase-N has been found to interfere with the induction and maintenance of hippocampal LTP and to produce spatial learning deficits in the Morris water maze paradigm.^8,76 Moreover, the frequency of NCAM polysialylated hippocampal neurons at the dentate infragranular border transiently increase at 10-12h following acquisition of either spatial or conditioned avoidance tasks.^22,31,77 These frequency changes are learning specific as they are not observed in animals rendered amnesic with either scopolamine or propofol.^23,84 Similar coincident frequency increase of polysialylated neurons occurs in layer II of the entorhinal and perirhinal cortex following spatial learning.^32,83

What about Neurogenesis in Learning?

Bromodeoxyuridine (BrdU) incorporation studies suggest that a proportion of the polysialylated neurons observed in the adult hippocampal dentate gyrus are recently generated¹⁰⁶ and necessary for odour discrimination.⁴⁰ Moreover, their depletion, following neurotoxic lesions, results in impaired trace conditioning of the eyeblink response, a hippocampal-dependent paradigm.¹⁰⁷ However, the learning-induced transient increase in polysialylated denate neuron frequency during the 12h post-training period does not appear to be associated with increased neurogenesis.³¹ Indeed, the specificity of BrdU as a neurogenic marker has been recently questioned.⁹⁰ In contrast to 3H-thymidine, BrdU is not a marker for cell division but rather a marker for DNA synthesis. This would explain the presence of BrdU-positive cells in layers other than those of the infragranular zone (Fig. 4).³¹ Moreover, the cells of the infragranular zone are remarkably heterogenous⁷⁵ and, to date, there has been no attempt to relate BrdU or PSA labelling with their neurotransmitter phenotype. These polysialylated neurons receive synaptic input and are distinguished from the mature neurons, located in the superficial granule cell layer, by showing paired pulse facilitation and having a lower threshold for induction of LTP.^126,129 In my view, the most likely functional significance of learning-induced transient increases in the polysialylated neurons of the dentate infragranular zone is to facilitate the dendritic elaboration of recently acquired neurons in response to the acquisition of novel behavioural repertoires.

Figure 4

Distribution of polysialylated and BrdU-labelled neurons in the hippocampal dentate gyrus in the 12h post-training period following acquisition of a passive avoidance paradigm. Panel A illustrates (ls) PSA-labelled neurons at the infragranular layer (arrows) (more...)

Perspective

The function of dendritic remodelling as a mechanism for the consolidation of information is still in its infancy. There is still no clear consensus as to whether spine or synapse frequency change accompanies memory formation. Aside from the consideration of differing tissue fixation and stereological procedures, the majority of studies have failed to take account of the fleeting nature of hippocampal information processing prior to its eventual consolidation within the neocortex.¹¹⁷ Moreover, the diverse nature of the learning paradigms employed is also likely to result in temporal phase shifts of synaptic dynamics. For example, synapse frequency change occurs within minutes following the induction of LTP124 as compared to the changes wrought at 6-8h following the acquisition of a spatial learning paradigm.86 Moreover, 24h after the induction of LTP there is little evidence of spine frequency change or at 6 days following extensive training in the water maze.^97,104 Studies on spine and synapse frequency change following behavioural adaptation must also be cognisant of the separate pathways and sub-regions of the medial temporal lobe that are involved in the processing of information. Spine frequency change has been observed in the dentate gyrus but not CA1 region of the hippocampal formation following successful acquisition of tasks dependent on this brain region.^37,86

The question of cell signalling from the extracellular environment to the nucleus of the neuron is central to how the brain modifies its structure and function to learn and remember. In this regard, ideal transmembrane signalling molecules should control the connections formed between neurons and govern cytoskeletal dynamics in a manner that regulates their morphology. CAMs are cell surface macromolecules that control cell-cell interactions during development of the nervous system by regulating such processes as neuronal adhesion and migration, neurite outgrowth, fasciculation, synaptogenesis and intracellular signalling.

There is now substantial evidence that CAMs are intimately associated with the molecular cascade that underpins the synaptic plasticity of memory consolidation and, moreover, their functions follow a defined sequence of events. The temporal involvement of CAMs in memory consolidation is dramatically illustrated by interventive studies using anti-L1 in chick avoidance conditioning.^103,123 In this paradigm L1 function is required at three discrete time periods over an 18h period. Again, with NCAM, and its PSA glycosylated variant, discrete periods of function are described for its role in acquisition, in a 6h post-training period that coincides with increased synapse production and, later at the 12h period.^{21,22,30,31,32,77,83,96,102} The fact that antibodies are ineffective in the intervening periods further supports the notion that CAMs have specific temporal actions in the molecular cascade of memory consolidation. Moreover, these experiments are consistent with the need for their extensive involvement in the processing of information within the medial temporal lobe prior to its re-distribution to multiple neocortical sites.

What is unclear about the role of CAMs in memory consolidation, however, is their suggested contribution to synapse connectivity pattern that is proposed to be generated by activity-dependent spine growth and de novo synapse formation. Indeed, the significance of de novo synapse formation as a functional correlate of memory consolidation is far from clear, as some studies have failed to equate this morphological associate with learning.37 Aside from the obvious consideration of differing tissue fixation procedures, failure to observe morphological change may relate to the temporal aspects of memory consolidation, as is exemplified by the CAM interventive studies. Although spine and synapse formation have been correlated with periods of CAM function in some studies,^22,85,86,102 others have failed to find an increased spine number but, rather, an increased frequency of synapses expressing greater levels of CAM.¹⁰⁴ In this regard, it is interesting to suggest that the increased NCAM labelling observed in the chick paradigm of avoidance conditioning, at a time sensitive to memory disruption with anti-L1 and anti-NCAM, may simply reflect selective retention of a synaptic population normally eliminated during the precocial development of this animal.^102,103,108

What the future seems to hold is the need to associate increased CAM functions, such as signalling, and their role in de novo synapse formation. Too often CAM function has been extrapolated from in vitro studies and their role in the adult nervous system may be significantly different. This view is supported by the numerous models of targeted deletion of CAM function that have no significant developmental outcome but frequently exhibit learning deficits.^16,33 Another example that supports a potential role for CAMs in synapse remodelling, as opposed to de novo synapse formation, comes from studies of peptide ligands with an affinity for the homophilic binding domain of NCAM.³⁰ In vitro, such peptides induce neuritogenesis,⁹³ a function that might predict an inherent cognition-enhancing property if the model of de novo synapse formation has relevance to memory consolidation. By contrast, these peptides produce a profound amnesia when administered during training or in the 6-8h post-training period in which anti-NCAM and spine formation is observed to occur following training.³⁰ A more parsimonious interpretation could be that these peptide ligands disrupt pre- to postsynaptic signalling necessary for synapse strengthening.

An attractive possibility is that transmembrane CAMs transmit activity-dependent change of intracellular-signalling across the synapse hence modulating the strength of cell-cell binding and thereby rapidly altering synaptic structure and efficacy. Although the expression patterns of N-cadherin, NCAM and L1 can be regulated by distinct patterns of action potentials,^51,52 their adhesive interactions across the synaptic cleft and in synaptic function has remained elusive. If expression of cell adhesion molecules can be regulated by activity, then newly synthesised molecules may participate in the formation and modification of synapses. For example, at certain synapses in the central nervous system, pre- and postsynaptic adhesion is mediated by N-cadherin that, upon depolarisation, dimerizes and becomes markedly protease resistant.¹¹⁹ Other in vitro studies have demonstrated activity-dependent strengthening of synapses to be dependent on integrins and/or the relative levels of post-synaptic, as opposed to pre-synaptic, NCAM.^14,19

In conclusion, CAMs can no longer be viewed as the structural scaffold of the synapse but as active participants that are involved in all aspects of its plasticity, including trans-synapse signalling and structural modification. Understanding these trans-synapse signalling mechanisms will be crucial in relating extracellular adhesive interactions to gene transcription and protein synthesis that is required for long-term changes in synaptic function.

Acknowledgements

The author_s work reviewed herein is currently supported by the EU 5th Framework Programme (QLRT-1999-02187) and basic research grants from Enterprise Ireland and the Health Research Board of Ireland.

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