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Synaptic mechanisms of memory loss: novel cell adhesion molecules as therapeutic targets

Final Report Summary - MEMSTICK (Synaptic mechanisms of memory loss: novel cell adhesion molecules as therapeutic targets)

Memory loss is a central symptom in different diseases, and represents a significant social and economic burden for a large percentage of European citizens. The molecular and neurobiological bases of memory deficits are largely unknown and there are currently no drugs available that can markedly decelerate or prevent memory decline. This consortium addresses this major problem by focusing on the role of novel synaptic cell adhesion molecules (CAMs; with a special focus on neuroplastin, nectins, SynCAM, neuroligin, neurexin, and NCAM, as well as in their molecular interactions with components of the extracellular matrix) in memory loss, and on the therapeutic value of targeting these CAMs to restore memory function and associated neurobiological mechanisms at the synaptic level. Memory loss is studied through a variety of animal models for stress, aging, psychiatric disorders, epilepsy and Alzheimer's disease. The final goal is the preclinical development and validation of mimetic peptides for these novel synaptic cell adhesion molecules as potential drug candidates to treat memory deficits or prevent memory decline. This project opens the research of memory function to a new set of molecular pathways for which their in vivo functions are largely unknown.

Project context:

The MEMSTICK proposal responded to the call HEALTH-2007-2.2.1-4: 'Memory loss: underlying mechanisms and therapy'. According to the call requirements, it aimed to the following:

1. Understanding mechanisms underlying memory loss. More specifically, it focused on the role of synaptic CAMs (neuroplastin, nectin 1 and 3, SynCAM, neurexin-neuroligin complexes, and NCAM) in memory formation and memory loss. In addition, it aimed at understanding the impact of these adhesion molecules at different neurobiological levels (i.e. biochemical, structural and functional).
2. Developing therapies to treat memory loss, by focusing on the development and testing of mimetic peptides targeting synaptic cell adhesion molecules that play key roles in synapse formation and stabilisation and in synaptic plasticity.
3. Investigating mechanisms and develop therapies in different conditions of memory loss, an endeavour that was pursued by using pre-clinical rodent models of psychiatric diseases, stress and aging, and epilepsy.

The view that changes in synaptic efficacy -and therefore in the functioning of neural circuits- underlie learning and memory processes is nowadays generally accepted, with compelling cumulative evidence indicating that memory formation involves changes in synaptic strength. Memory is a complex cognitive process whose study requires to simultaneously considering not only the encoding and consolidation of information, but also the abilities to acquire (learning) and to get access to stored (retrieval) information. Memory involves different phases and types which imply a differential functioning of specific brain regions. Most life-impairing human conditions involving memory deficits -particularly those addressed by the current proposal: aging, stress, and psychiatric and medial temporal lobe epilepsy- are related to declarative / explicit and working memory types and, therefore, imply alterations at the level of the hippocampus and prefrontal cortex. Memory disturbances induced by stress and characteristic of certain psychiatric diseases -notably posttraumatic stress disorder, but also anxiety and depression- are also related to amygdala malfunction -frequently hyperfunction. The current idea is that cell death per se cannot explain memory loss observed in aging, stress-induced cognitive disturbances, or psychiatric conditions. Instead, perturbations in synaptic plasticity and neurocircuitry function are believed to cause deficits in long-term (declarative / explicit) memory and working memory.

The role of synaptic cell adhesion molecules in memory function

Information is encoded in the central nervous system through neural networks functionally connected by synapses. Synapses mediate communication between individual neurons, participate in the computation of neuronal networks and store information through long-term modifications of strength and structure. Synaptic activity can affect -enhancing or depressing- subsequent synaptic strength, a phenomenon known as 'activity-dependent synaptic plasticity'. Activity-dependent synaptic plasticity, in addition of playing key roles in normal brain function, is also essential for recovery from brain malfunction. Recent compelling evidence indicates that, together with conventional synaptic transmission mechanisms, CAMs (which are essential elements for shaping and maintaining neural circuitry during development) are major players of synaptic plasticity and memory function in the adult brain. These CAMs include neural cell adhesion molecules of the immunoglobulin (Ig) superfamily (e.g. NCAM and L1), N- and E-cadherins and integrins.

A variety of CAMs participate in the establishment, maintenance, and modulation of synaptic contacts throughout the nervous system, and play essential roles in both short- and long-lasting forms of synaptic plasticity through different mechanisms:

(i) by affecting adhesive synaptic strength: changes in synaptic adhesion induced by CAMs can affect the concentration of glutamate (or other neurotransmitters) at the synapse, glutamate receptor signalling and other signalling pathways, and glutamate receptor expression; all these can have a major impact on synaptic physiology and have been critically implicated in the mechanisms of memory formation;
(ii) by regulating the formation of new synapses: CAMs, and more precisely 'synaptic CAMs', are critical for the regulation of synapse number, since they allow new synapse assembly and are fundamental for synapse maintenance. Both new synapse formation and synaptic loss are fundamental properties of the brain not only during development, but also in adulthood, and are critically implicated in the mechanisms of memory function and its pathologies;
(iii) by modulating signal transduction at the synapse: although CAMs have long been surmised to play a role in holding the contacts together, it has only recently been discovered that the neural CAMs are also major players in modulation of signal transduction at the synapse.

Thus, CAMs are major regulators of synaptic number, size and strength. However, many of the CAMs studied so far are not synapse specific. Very recently, a number of synapse specific CAMs have been described and in vitro experiments highlight their important role in synapse formation, maintenance and synaptic plasticity. The MEMSTICK consortium has focused on the understanding of the role of novel synaptic CAMs in memory formation and memory loss, as well as in a thorough characterisation of NCAM as potential therapeutic target.

The role of synaptic cell adhesion molecules in synaptic plasticity

Assembly and modulation of synapses rely heavily on several neuronal CAMs. Members of various CAM families are localised in the synaptic junctions. Recently, a number of synapse-specific CAMs has been identified. The most intriguing examples of the 'novel' synaptic Ig CAMs are neuroplastin, the nectin family, and the neurexin / neuroligin recognition complex. It is important to emphasise that synaptically localised CAMs should be regarded not as static participants whose task is just to preserve the structural scaffolding upon which synaptic signalling takes place but, instead, as active players in the signalling process itself, since they are able to modulate structural and functional components of synaptic plasticity.

(i) Synaptic Ig CAMs:
Their common feature is their relatively short extracellular parts consisting of only three Ig modules. Interestingly, the first Ig modules of all these CAMs are apparently involved in homophilic and/or heterophilic binding. The molecular mechanisms of cell adhesion are currently unknown for these CAMs. For this project, we selected to mainly focus on the following novel synaptic Ig CAMs:

(i) Neuroplastin, that is expressed in two forms of different molecular weights, Np55 and NP65, the latter being brain-specific. Np65 is exclusively localised to the pre- and particularly postsynaptic membranes, mediating homophilic (self-self) interactions and contributing to synaptogenesis and synapse stabilisation. Evidence for its involvement in memory function comes from the finding that long-term potentiation (LTP) of synaptic strength increases the levels of neuroplastin-65 within a postsynaptic density (PSD)-enriched fraction, and treating hippocampal slices with antibodies against neuroplastin-65 impairs L-LTP.
(ii) Nectin-1 and nectin-3 are particularly interesting members of the nectin family of molecules. All nectins and involved in homophilic and/or heterophilic interactions. Nectin-1 is widely expressed in the nervous system, both in humans and mice, and it interacts in trans with nectin-3. They are asymmetrically distributed pre- and postsynaptically. Inhibition of interactions between nectin-1 and nectin-3 in neuronal cultures reduces the size of synapses, but increases their number. In the adult hippocampus, nectin-1 and nectin-3 are both expressed at puncta adherentia and at synaptic junctions between mossy fiber terminals and dendrites of pyramidal cells where they are present on pre-and postsynaptic membranes, respectively. Interestingly, computations at this level of the hippocampus are known to be critical for memory function, and these hippocampal synapses have also greatly affected under conditions of memory loss included in this proposal, such as chronic stress, aging and models of psychiatric disorders -notably depression.
(iii) NCAM, included in the proposal because it shows a high synaptic expression and has been shown to be critical for synaptic plasticity and memory formation.

(ii) The Neurexin-neuroligin trans-synaptic adhesion complexes have revealed highly important for cell adhesion, synapse formation and cognitive function. Presynaptic neurexins bind postsynaptic neuroligins promoting adhesion and signalling the recruitment of presynaptic and postsynaptic molecules to form a functional synapse. Neuroligins can induce the formation of fully functional presynaptic terminals in contacting axons. Neurexins can induce postsynaptic differentiation and clustering of receptors in dendrites. Their interaction has the exceptional ability to act as a bi-directional trigger of synapse formation. Neurexin (presynaptic) interacts with neuroligin 1 that is postsynaptically expressed at glutamatergic synapses, whereas neurexin (presynaptic) interacts with neuroligin 2 that is postsynaptically expressed at GABAergic synapses. These interactions are critical for the discrimination between excitatory (glutamatergic) and inhibitory (GABAergic) synapses; a mechanism that is disrupted in some neuropsychiatric conditions. Importantly, genetic studies have pointed out a link between the genes encoding for neuroligins and autism.

CAMs mimetic peptide s as therapeutic drugs in memory loss

Although there is increasing evidence for a potential role of molecules involved in synaptic plasticity, such as neural cell adhesion molecules and their ligands in memory loss, knowledge on these mechanisms and their potential therapeutic efficacy is still scarce. MEMSTICK proposed the development of mimetic peptides targeting cell-cell adhesion complexes as a novel approach towards the development of new strategies for the treatment of dysfunctional plasticity, learning and memory.

Previous work by some of the participants in the consortium (partners ENKAM, Neoloch and EPFL) had shown that peptides derived from neural cell adhesion molecules (NCAM and L1) are biologically active in vivo both at the cognitive level and protecting against neurodegeneration (Berezin V and Bock E., 2004; Cambon et al., 2004; Klementiev et al., 2007). The peptide FGL, mimicking NCAM interaction with the fibroblast growth factor receptor (FGFR) had been demonstrated to penetrate the blood brain barrier (Secher et al., 2006) and tested in humans (Anand et al., 2007).

Therefore, the MEMSTICK consortium aimed at applying the same approach to the development of peptides for other novel synaptic CAMs and to investigate their potential therapeutic impact and neurobiological effectors in animal models of memory loss. As neurobiological effectors, the MEMSTICK consortium aimed at focusing on extracellular matrix mechanisms, structural mechanisms of synaptic plasticity, and functional electrophysiology. As to the animal models of memory loss, the consortium addressed a broad range of conditions, from models of psychiatric disorders -such as anxiety or depression-, to stress and stress mechanisms, ageing and medial temporal lobe epilepsy.

Project objectives:

The main goal of the MEMSTICK consortium is to investigate the role of novel synaptic cell adhesion molecules in memory loss, and the therapeutic value of targeting these adhesion molecules to restore memory function and associated neurobiological mechanisms at the synaptic level.

This is pursued through the following specific objectives:

- To identify peptides mimicking novel synaptic CAMs and to evaluate their effectiveness to affect key cellular, molecular and functional aspects of neuronal and synaptic plasticity.
- To characterise the pattern of expression of novel synaptic CAMs, at the level of neural circuits and synapses, under a variety of conditions involving memory loss.
- To validate therapeutic opportunities in vivo of mimetic peptides for novel synaptic CAMs to repair memory loss in pre-clinical mouse models for psychiatric disorders, stress and aging, epilepsy and the neurodegenerative condition of Alzheimer's disease.
- To identify key neurobiological (molecular, structural and functional) mechanisms involved in the beneficial effects of mimetic peptides in models of memory loss in specified brain regions.

Project results:

The major findings of the project can be summarised as follows:

Peptide development and in vitro characterisation

Several synaptic cell adhesion molecules were identified as targets for peptide development. In a first step, the structural characteristics at the molecular level of each selected adhesion molecule were resolved either through a first crystallisation step followed by X-ray analyses, or through nuclear magnetic resonance (NMR) analysis. These approaches allowed revealing those parts of the molecular structures of these adhesion molecules that are essential for the interaction and/or binding with other molecules. This information was then used as the basis to design new peptide molecules with similar sequences to these binding domains. Whenever the designed and synthesised peptide was proved to be successful though surface plasmon resonance analyses to interact with relevant binding partners, this peptide was selected for further characterisation.

Thus, a number of synaptic CAMs and their ligands / counter-receptors were recombinantly expressed either as complete proteins or in fragments for the study of structure and receptor-ligand interactions, including Neuroplastin-55 (Owczarek et al., 2010), Neuroplastin-65 (Owczarek et al., 2011), Nectin-1 and Nectin-3. Several homophilic and heterophilic binding sites were identified. For identification of new heterophilic partners of various synaptic CAMs a number of genetic manipulations have been applied to neuronal cultures including the use of shRNA of beta-neurexin, neuroligin-1. In order to determine the association of specific synaptic CAMs with specific structural (morphological) and functional aspects of the synapse, a number of antibodies were developed, including ones to identify neuroligin-1, neuroligin-2, and nectin-1.

Subsequently, the structure-based design and molecular modelling were used to design and manufacture mimetic peptides. The following mimetic peptides were designed: Narpin [mimetic of the heterophilic binding site of neuroplastin-55 for the fibroblast growth factor receptor (FGFR)]; Enplastin (mimetic of the homophilic binding site of neuroplastin-65); Nectide (mimetic of the heterophilic binding site of nectin-1 for the FGFR); Neurexide (mimetic of the heterophilic binding site of neurexin-1? for neuroligin-1); NLGN-peptide (mimetic of the heterophilic binding site of neuroligin-1 for neurexin); NLGN2-peptide (mimetic of the heterophilic binding site of neuroligin-2 for neurexin-1); and Enreptin (mimetic peptide of the heterophilic binding site of FGFR for NCAM). The peptides were synthesised as dimers or tetramers. To validate that peptides mimic the corresponding binding sites in CAMs, surface plasmon resonance (SPR) analysis were performed.

All identified mimetic peptides were characterised for their in vitro activity using various cell biological, electrophysiological and biochemical methods. Thus, the Narpin peptide induces phosphorylation of FGFR1 - a molecule known to be essential in processes linked to learning and plasticity - and to induce FGFR-dependent neurite outgrowth).

The Enplastin peptide inhibits neuroplastin-65 mediated cell adhesion, as reflected by inhibition by the peptide of neuroplastin-65 mediated neurite outgrowth. Moreover, enplastin affects cell signaling mechanisms involved in plasticity and memory function.

As to other peptides, the Nectide peptide also induces phosphorylation of FGFR1, as well as neurite outgrowth. The Neurexide peptide induces neurite outgrowth when synthesised as tetramer or dimer, but not as a monomer, and it also promotes synaptogenesis and cell survival. The NLGN-peptide induces neurite outgrowth depending upon expression of neurexin-1. The NLGN2-peptide induces, as well, neurite outgrowth. The Enreptin peptide induces neurite survival and outgrowth, the latter depending on NCAM expression and activation of FGFR and Fyn. In addition, the NCAM-mimetic peptide Plannexin facilitates synaptic transmission in the CA1 hippocampal area, without affecting transmission in the dentate gyrus.

The involvement of novel synaptic cell adhesion molecules in memory formation
The MEMSTICK consortium has devoted very strong efforts to the development and characterisation of animal models of memory loss, including a variety of models based on early life stress (both in rats and mice), models of chronic stress and depression induced in adulthood, genetic mutations for the expression of specific CAMs (either conditional KO mice or brain-region specific genetic alterations through viral vector delivery), as well as models of epilepsy and Alzheimer's disease.

However, given the scarce knowledge available in the literature about the role of the novel synaptic cell adhesion molecules in memory formation, a considerable effort was addressed to evaluate time-dependent regulation of the expression of these CAMs following learning and memory under normal conditions. The results showed a time- and region-dependent regulation of neuroplastin (Np65) and nectin1 expression in the hippocampus during the consolidation period in which recently acquired information is processed to become a long-term memory (Fantin et al., in preparation). Furthermore, in vitro approaches showed that stimulating the synaptic machinery lead to partial cleavage of dystroglycan and N-cadherin. These findings support the involvement of these molecules in the neural remodeling processes linked to long-term memory formation.

Impact of conditions involving memory loss on novel synaptic cell adhesion molecules

The investigation of expression patterns of these synaptic cell adhesion molecules in different animal models of memory loss has revealed quite important changes. Early life stress in rodents was found to have a strong impact on animals' behaviour in adulthood, inducing increased anxiety- and depression-like behaviours, as well as memory deficits in spatial learning tasks. In parallel, these animals also show decreased hippocampal expression of several of the synaptic cell adhesion molecules studied molecules, including nectin1, nectin3, neurexin and neuroligin1 (Kohl et al., in preparation; Fantin et al., in preparation). Likewise, marked alterations were observed in different models of psychiatric disorders. For example, a depression model based on chronic stress in adulthood, and known to impair learning and memory in hippocampus-dependent tasks, was found to induce marked reduction in hippocampal expression of nectin1, nectin3, neuroligin2 and neuroligin3 (Fantin et al., in preparation). In a model of schizophrenia, based on the transitory induction of glutathione impairment during early life, an inverted pattern of expression was found for the two neuroplastin isoforms (Np55 and Np65) in hippocampus (decreased) and prefrontal cortex (increased). In rat models of epilepsy, which are dramatically impaired in their learning and memory capabilities, the hippocampus was found to display reduced levels of NCAM, nectin1, nectin3 and N-cadherin (Inoztrosa et al., in preparation). In genetic mouse models of Alzheimer's disease, these molecules showed an altered pattern of hippocampal expression, some of them increasing (NCAM, nectin3, neuroplastin and SynCAM), while other decreasing (neuroligin1). Alterations in the regulation of these molecules following a cognitive challenge were found in the AD mouse models investigated.

One important finding was related to mechanisms linking chronic stress with the marked structural and molecular changes occurring in the hippocampus in association with spatial memory deficits. Thus, whereas in chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of the hippocampal CA3 pyramidal neurons reduced, stressed mice with forebrain Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory (Wang et al., 2010).

Importantly, the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Thus, the expression of hippocampal nectin-3, especially in the CA3 stratum radiatum where dendritic arborisation was reduced by chronic stress, was down-regulated in stressed wild-type but not stressed CRHR1Camk2aCre mice. This is the first experimental evidence showing that hippocampal nectin-3 expression is regulated by chronic stress and modulated by CRH-CRHR1 signaling, which is associated with dendritic remodeling and cognitive function. Additionally, based on its specific spatial distribution pattern, these data suggests that nectin-3 is a potential molecular marker for compromised CA3 neurons in response to chronic stress.

These findings underscore an important role for Nectin-3, in conjunction with forebrain CRH-CRHR1 signaling, in modulating chronic stress-induced cognitive, structural and molecular adaptations. Disrupted function of the nectin-afadin complex would lead to dendritic atrophy and spine modifications, which in turn impair hippocampus-dependent learning and memory. Importantly, in another study, Nectin-3 was also found to be reduced after a 3-week chronic stress protocol in rats, in association with CA1 cognitive deficits and deficits in social behaviour. Administration of AAV to overexpress Nectin-3 in the hippocampus was efficient to recover those deficits, without affecting chronic stress effects in aggressive behaviours. Thus, the disruption of Nectin-3-mediated adhesion appears as a critical mechanism whereby stress induces structural and functional alterations in the hippocampus.

Nectins, along with NCAM, were also markedly reduced in rat models of temporal lobe epilepsy epilepsy, a condition that also involves cognitive impairment. While different experimental models have been used to characterise TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. The Consortium evaluated the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris watermaze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amygdala concur with spatial memory deficits observed in epileptic rats. The results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se (Inostroza et al., in press).

Another important finding that appeared repeatedly across different stress models is the modulation of the neuroligin family of molecules. Chronic stress models associated to cognitive and social deficits were found to result in alterations in neuroligin-2 or neuroligin-3 (Fantin et al., in preparation).

In addition, the down-regulation of NCAM in the hippocampus by chronic stress, previously reported in rat studies, was confirmed in mice (Bisaz et al., 2011). A novel observation with regards to this molecule was its enhancement in the amygdala following chronic stress, an effect that was related to the potentiation of fear conditioning by stress (Bisaz and Sandi, 2010).

Altogether, the findings obtained by this consortium underscore the synaptic cell adhesion molecules as critically modulated by learning experiences and showing a selective altered pattern of expression (frequently decreased) in learning-relevant regions (notably the hippocampus) under a variety of conditions (animal models of stress and aging, psychiatric disorders, epilepsy and Alzheimer's disease) presenting memory loss.

Therapeutic relevance of targeting synaptic cell adhesion molecules to treat memory loss

The important modulation found in the pattern of expression of the synaptic cell adhesion molecules under study both during consolidation of memory in normal animals and under conditions of memory loss provides strong support for an involvement of these molecules in memory processes and memory dysfunction, placing them as promising candidates for therapeutic purposes.

As indicated above, the rationale to target the Nectin family was provided by studies in both mice (Wang et al., 2011) and rats (Fantin et al., submitted). In the rat study, chronically stressed rats showed cognitive and emotional alterations along with a reduction in Nectin-3 levels in the hippocampus. When treated with AAV to overexpress Nectin-3 in the hippocampus, chronically stressed rats showed a recovery of those behavioural deficits, without concomitant effects in altered aggressive behaviours also induced by chronic stress (Fantin et al., submitted).

The MEMSTICK consortium also explored the potential of tackling NCAM to improve memory. Although this molecule has been much more studied than the other CAMs included in the project, its complexity both at the structural and functional levels - with multiple domains engaged in a variety of actions - raises the question as to which NCAM fragment should be targeted to improve cognition. The development of synthetic NCAM mimetic peptides that mimic NCAM sequences relevant to specific interactions allow identifying the most promising targets within NCAM. Recently, a decapeptide ligand of NCAM-plannexin, which mimics a homophilic trans-binding site in Ig2 and binds to Ig3- was developed as a tool for studying NCAM's trans-interactions. We have investigated plannexin's ability of to affect neural plasticity and memory formation. We found that plannexin facilitates neurite outgrowth in primary hippocampal neuronal cultures and improves spatial learning in rats, both under basal conditions and under conditions involving a deficit in a key plasticity-promoting posttranslational modification of NCAM, its polysialylation (Kraev et al., under revision).

In addition, the performance of both conditional NCAM-deficient mice and chronically stressed wild-type mice in the water maze was improved by post-training injection of the NCAM mimetic peptide, FGL (Bisaz et al., 2011). These findings further support the functional involvement of NCAM in chronic stress-induced alterations and highlight this molecule as a potential target to treat stress-related cognitive disturbances.

Neurobiological mechanisms involved in the memory enhancing properties of selected peptides

The consortium has devoted big efforts to understand the cellular and synaptic mechanisms that operate during the storage of memories, impairment and restoration.

In particular, the decreased levels observed for Nectin 3 in the CA1 field of stressed animals were found to correlate with increased gelatinase activity, indicating a role for metalloproteinase-9 (MMP-9) activity. In addition, our results point at MMP-9 directly affecting morphological synaptic plasticity by producing spine elongation in-vitro and in-vivo. The peptide FGL, found to restore memory under conditions of memory loss, was found to enhance neuroglial structural support of the synapse.

Importantly, the consortium identified key neurobiological mechanisms related to the therapeutic effects of the NCAM mimetic peptide plannexin that was shown to restore memory deficits (Kraev et al., under revision). Notably, plannexin was found to enhance hippocampal synaptic transmission in CA1, where it also increases the number of mushroom spines and the synaptic expression of the AMPAR subunits GluA1 and GluA2.

These findings provide compelling evidence that plannexin is an important facilitator of synaptic functional, structural and molecular plasticity in the hippocampal CA1 region, highlighting the fragment in NCAM's Ig3 module where plannexin binds as a novel target for the development of cognition-enhancing drugs.

Additionally, important insights were obtained regarding mechanisms underlying deficits in episodic-like memory in epilepsy, involving a disturbance on the coordination of electrophysiological (theta) activity in the hippocampus (between CA1 and the dentate gyrus).

The two small and medium-sized enterprise (SME) biotech companies (ENKAM, NEOLOCH) involved are actively engaged in the translation of the knowledge developed by the consortium into promising therapeutic targets.

In summary, work developed by the MEMSTICK consortium has provided major progress in a topic that, despite being highly promising as to its implications on memory function, was largely unknown. The consortium has provided important insights about the modulation of synaptic cell adhesion molecules under conditions of memory loss and showed that targeting some of these molecules (notably, Nectin-3 and NCAM) with pharmacological or genetic approaches is a promising strategy to restore memory deficits. Finally, key relevant mechanisms of action were revealed opening new venues for future studies to refine strategies to treat memory problems.

Potential impact:

Work developed by the MEMSTICK consortium has provided major progress in the understanding of neurobiological mechanisms involved in memory formation and memory loss, identified key molecular targets (notably, Nectin-3 and NCAM) among the synaptic cell adhesion molecules that effectively overcome conditions of memory loss, and showed key relevant mechanisms of action associated to treatment effectiveness (notably, changes in synaptic shape and in synaptic expression of glutamate receptors). Work in the consortium has identified new molecular targets and peptide approaches with a promising profile to restore memory deficits. In addition, the results of the consortium open new venues for future studies to refine strategies to treat memory problems; the mimetic peptides developed and identified as particularly relevant can now be used as target goals to treat memory deficits associated to stress, aging and psychiatric disorders.

Thus, the MEMSTICK project has contributed to the goals remarked in the Seventh Framework Programme (FP7) HEALTH programme's policy to advance our understanding on how to more efficiently promote good health, to prevent and treat major diseases, and to deliver healthcare by supporting world-class collaborative research with specific attention to translational research. Specifically, the MEMSTICK consortium has addressed one of the central sections of the FP7 Work Programme 'Translating research for human health', by increasing knowledge of biological processes and mechanisms involved in normal health and in specific disease situations, to transpose this knowledge into clinical applications. As indicated above, the two SME biotech companies (Enkam, Neoloch) involved are actively engaged in the translation of the knowledge developed by the consortium into promising therapeutic targets.

Moreover, the MEMSTICK consortium has substantially improved current knowledge of brain function and dysfunction (from molecules to cognition), addressing mechanisms and targets relevant for neurological and psychiatric disorders and with a focus on restorative therapeutic approaches. Translational research has been at the core of the project. Knowledge developed by the consortium provides a very strong support to the importance of these molecules and neurobiological mechanisms as well as for the therapeutic importance of synaptic cell adhesion molecules to treat memory deficits. The two biomedical SMEs are immediate direct users of the knowledge. In addition, the knowledge developed in the consortium can contribute to other future actions (promoted directly by these companies or by other potential bodies) via the different dissemination mechanisms (i.e. publications, conferences, patents). These actions have, thus, a strong potential for increasing the competitiveness and boosting the innovative capacity of European health-related industries and business.

Furthermore, the consortium has succeeded in strengthening the European network of groups working in memory problems and in the link with cell adhesion mechanisms and treatments by reinforcing many collaborations between the partners involved in MEMSTICK and by enhancing interactions with other European groups that were awarded, in parallel, with a FP7 project under the same call (as an illustrative example, it is the satellite meeting to FENS on 'Memory' hold in July 2011, in Amsterdam, by the three consortia: MEMOSAd, MEMOLOAD and MEMSTICK). Moreover, the consortium has supported leading roles of women in science (with the coordinator and three project leaders out of a total of eight groups being women and having a strong representation in the decision-making and managing.

The MEMSTICK consortium implemented the exploitation of project results by means of patents and products. In particular the following exploitation tracks constituted the structure of the exploitation objectives of the project:

- Exploitation of the obtained scientific results towards commercial and societal benefit including the detailed analysis of possible therapeutic indications and selection of compounds for further preclinical development including toxicology.
- Contribution to the European Commission (EC)'s goal of increasing the international competitiveness of Europe, in general, and in the health and medicine markets in particular.
- Establishment of a roadmap for the selected compounds promoting plasticity and enhancing memory and the commercialisation of related products.

Continuous feedback on the adequacy of innovative approaches employing novel synaptic cell adhesion molecules as therapeutic targets allowed to directly address the research needs of the European industry and societal groups concerned.


Contact persons:

Prof. Carmen Sandi
Telephone: +41-216-939534
Fax: +41-216-939636

Dr Kirsten Leufgen

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