Cell Adhesion, the Backbone of the Synapse: ��Vertebrate�� and ��Invertebrate�� Perspectives

Synapses are asymmetric intercellular junctions that mediate neuronal communication. The number, type, and connectivity patterns of synapses determine the formation, maintenance, and function of neural circuitries. The complexity and specificity of synaptogenesis relies upon modulation of adhesive properties, which regulate contact initiation, synapse formation, maturation, and functional plasticity. Disruption of adhesion may result in structural and functional imbalance that may lead to neurodevelopmental diseases, such as autism, or neurodegeneration, such as Alzheimer''s disease. Therefore, understanding the roles of different adhesion protein families in synapse formation is crucial for unraveling the biology of neuronal circuit formation, as well as the pathogenesis of some brain disorders. The present review summarizes some of the knowledge that has been acquired in vertebrate and invertebrate genetic model organisms.Synapses are asymmetric, intercellular junctions that are the basic structural units of neuronal transmission. The correct development of synaptic specializations and the establishment of appropriate connectivity patterns are crucial for the assembly of functional neuronal circuits. Improper synapse formation and function may cause neurodevelopmental disorders, such as mental retardation (MsR) and autism spectrum disorders (ASD) (McAllister 2007; Sudhof 2008), and likely play a role in neurodegenerative disorders, such as Alzheimer''s disease (AD) (Haass and Selkoe 2007).At chemical synapses (reviewed in Sudhof 2004; Zhai and Bellen 2004; Waites et al. 2005; McAllister 2007; Jin and Garner 2008), the presynaptic compartment contains synaptic vesicles (SV), organized in functionally distinct subcellular pools. A subset of SVs docks to the presynaptic membrane around protein-dense release sites, named active zones (AZ). Upon the arrival of an action potential at the terminal, the docked and “primed” SVs fuse with the plasma membrane and release neurotransmitter molecules into the synaptic cleft. Depending on the type of synapse (i.e., excitatory vs. inhibitory synapses), neurotransmitters ultimately activate an appropriate set of postsynaptic receptors that are accurately apposed to the AZ.Synapse formation occurs in several steps (Fig. 1) (reviewed in Eaton and Davis 2003; Goda and Davis 2003; Waites et al. 2005; Garner et al. 2006; Gerrow and El-Husseini 2006; McAllister 2007). Spatiotemporal signals guide axons through heterogeneous cellular environments to contact appropriate postsynaptic targets. At their destination, axonal growth cones initiate synaptogenesis through adhesive interactions with target cells. In the mammalian central nervous system (CNS), immature postsynaptic dendritic spines initially protrude as thin, actin-rich filopodia on the surface of dendrites. Similarly, at the Drosophila neuromuscular junction (NMJ), myopodia develop from the muscles (Ritzenthaler et al. 2000). The stabilization of intercellular contacts and their elaboration into mature, functional synapses involves cytoskeletal arrangements and recruitment of pre- and postsynaptic components to contact sites in spines and boutons. Conversely, retraction of contacts results in synaptic elimination. Both stabilization and retraction sculpt a functional neuronal circuitry.Open in a separate windowFigure 1.(A–C) Different stages of synapse formation. (A) Target selection, (B) Synapse assembly, (C) Synapse maturation and stabilization. (D–F) The role of cell adhesion molecules in synapse formation is exemplified by the paradigm of N-cadherin and catenins in regulation of the morphology and strength of dendritic spine heads. (D) At an early stage the dendritic spines are elongated from motile structures “seeking” their synaptic partners. (E) The contacts between the presynaptic and postsynaptic compartments are stabilized by recruitment of additional cell adhesion molecules. Adhesional interactions activate downstream pathways that remodel the cytoskeleton and organize pre- and postsynaptic apparatuses. (F) Cell adhesion complexes, stabilized by increased synaptic activity, promote the expansion of the dendritic spine head and the maturation/ stabilization of the synapse. Retraction and expansion is dependent on synaptic plasticity.In addition to the plastic nature of synapse formation, the vast heterogeneity of synapses (in terms of target selection, morphology, and type of neurotransmitter released) greatly enhances the complexity of synaptogenesis (reviewed in Craig and Boudin 2001; Craig et al. 2006; Gerrow and El-Husseini 2006). The complexity and specificity of synaptogenesis relies upon the modulation of adhesion between the pre- and postsynaptic components (reviewed in Craig et al. 2006; Gerrow and El-Husseini 2006; Piechotta et al. 2006; Dalva et al. 2007; Shapiro et al. 2007; Yamada and Nelson 2007; Gottmann 2008). Cell adhesive interactions enable cell–cell recognition via extracellular domains and also mediate intracellular signaling cascades that affect synapse morphology and organize scaffolding complexes. Thus, cell adhesion molecules (CAMs) coordinate multiple synaptogenic steps.However, in vitro and in vivo studies of vertebrate CAMs are often at odds with each other. Indeed, there are no examples of mutants for synaptic CAMs that exhibit prominent defects in synapse formation. This apparent “resilience” of synapses is probably caused by functional redundancy or compensatory effects among different CAMs (Piechotta et al. 2006). Hence, studies using simpler organisms less riddled by redundancy, such as Caenorhabditis elegans and Drosophila, have aided in our understanding of the role that these molecules play in organizing synapses.In this survey, we discuss the roles of the best characterized CAM families of proteins involved in synaptogenesis. Our focus is to highlight the complex principles that govern the molecular basis of synapse formation and function from a comparative perspective. We will present results from cell culture studies as well as in vivo analyses in vertebrate systems and refer to invertebrate studies, mainly performed in Drosophila and C. elegans, when they have provided important insights into the role of particular CAM protein families. However, we do not discuss secreted factors, for which we refer the reader to numerous excellent reviews (as for example Washbourne et al. 2004; Salinas 2005; Piechotta et al. 2006; Shapiro et al. 2006; Dalva 2007; Yamada and Nelson 2007; Biederer and Stagi 2008; Salinas and Zou 2008).     

Do Conflict Resolution and Recovery Predict the Survival of Adolescents' Romantic Relationships?

Numerous studies have shown that being able to resolve and recover from conflicts is of key importance for relationship satisfaction and stability in adults. Less is known about the importance of these relationship dynamics in adolescent romantic relationships. Therefore, this study investigated whether conflict resolution and recovery predict breakups in middle adolescent couples. Couples who are able to resolve and recover from conflict were expected to demonstrate a lower probability of breaking up. In total, 80 adolescent couples (M age = 15.48, SD = 1.16) participated in a 4-wave prospective questionnaire and observational study, with one year between measurements. In addition to self-report measures, adolescents were observed in real-time during conflicts with their partners. Multilevel Proportional Hazard analyses revealed that, contrary to the hypothesis, conflict resolution and conflict recovery did not predict the likelihood of breakup. Survival differences were not attributable to conflict resolution or conflict recovery. More research is needed to consider the unique relationship factors of adolescent romantic relationships to determine why some relationships survive while others do not.     

The Futility of Futility: Death Causation is the ��Elephant in the Room�� in Discussions about Limitation of Medical Treatment

The term “futility” has been widely used in medical ethics and clinical medicine for more than twenty years now. At first glance it appears to offer a clear-cut categorical characterisation of medical treatments at the end of life, and an apparently objective way of making decisions that are seen to be emotionally painful for those close to the patient, and ethically, and also potentially legally hazardous for clinicians. It also appears to deal with causation, because omission of a futile treatment cannot surely be a cause of death. The problem is that futility can be argued to be a “false friend”, in that it gives an appearance of representing a reliable conceptual basis, in ethics, for limitation of medical treatment—usually in the context of dying—without actually doing so. In fact, the concept of futility is a conflation of clinical judgement about outcomes of treatment and the quality or even value of life, and has really failed to contribute much to the advancement of decision-making and hence care at the end-of-life. It also has the capacity to medicalise the personal space. Deliberations about the likely outcomes of medical treatment are necessary, and medical expertise is pivotal. However, futility is argued to have a better future in partnership with a broad social action agenda about the process of dying, such as that articulated in health promoting palliative care, as a basis for better “death-ways” in the 21st century (Kellehear 2005). Medicine needs to more honest and upfront about its limits, as death is, after all, the elephant in everybody's room.     

Telomere-Specialized Retroelements in Drosophila: Adaptive Symbionts of the Genome,Neutral, or in Conflict?

Linear chromosomes shorten in every round of replication. In Drosophila, telomere-specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head-to-tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere-specialized LINE lineages across Drosophila. There appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere-specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive.     

Components of the Basal Lamina and Dystrophin�CDystroglycan Complex in the Neurointermediate Lobe of Rat Pituitary Gland: Different Localizations of ��-Dystroglycan, Dystrobrevins, ��1-Syntrophin, and Aquaporin-4

The so-called neurointermediate lobe is composed of the intermediate and neural lobes of the pituitary. The present immunohistochemical study investigated components of the basal lamina (laminin, agrin, and perlecan), the dystrophin–dystroglycan complex (dystrophin, β-dystroglycan, α1-dystrobrevin, β-dystrobrevin, utrophin, and α1-syntrophin), and the aquaporins (aquaporin-4 and -9). Glia markers (GFAP, S100, and glutamine synthetase) and components of connective tissue (collagen type I and fibronectin) were also labeled. In the neurohypophysis, immunostaining of basal lamina delineated meningeal invaginations. In these invaginations, vessels were seen to penetrate the organ without submerging into its parenchyma. On the parenchymal side of the invaginations, β-dystroglycan was detected, whereas utrophin was detected in the walls of vessels. Immunostaining of α1-dystrobrevin and α1-syntrophin did not delineate the vessels. The cells of the intermediate lobe were fully immunoreactive to α1-dystrobrevin and α1-syntrophin, whereas components of the basal lamina delineated the contours of the cells. GFAP-immunoreactive processes surrounded them. Aquaporin-4 localized at the periphery of the neurohypophysis, mainly adjacent to the intermediate lobe but not along the vessels. It colocalized only partially with GFAP and not at all with α1-syntrophin. Aquaporin-9 was not detected. These results emphasize the possibility that the components of the dystrophin–dystroglycan complex localize differently and raise the question about the roles of dystrobrevins, α1-syntrophin, and aquaporin-4 in the functions of the intermediate and neural lobes, respectively. (J Histochem Cytochem 58:463–479, 2010)     

The AP-3 �� Adaptin Mediates the Biogenesis and Function of Lytic Vacuoles in Arabidopsis

Plant vacuoles are essential multifunctional organelles largely distinct from similar organelles in other eukaryotes. Embryo protein storage vacuoles and the lytic vacuoles that perform a general degradation function are the best characterized, but little is known about the biogenesis and transition between these vacuolar types. Here, we designed a fluorescent marker–based forward genetic screen in Arabidopsis thaliana and identified a protein affected trafficking2 (pat2) mutant, whose lytic vacuoles display altered morphology and accumulation of proteins. Unlike other mutants affecting the vacuole, pat2 is specifically defective in the biogenesis, identity, and function of lytic vacuoles but shows normal sorting of proteins to storage vacuoles. PAT2 encodes a putative β-subunit of adaptor protein complex 3 (AP-3) that can partially complement the corresponding yeast mutant. Manipulations of the putative AP-3 β adaptin functions suggest a plant-specific role for the evolutionarily conserved AP-3 β in mediating lytic vacuole performance and transition of storage into the lytic vacuoles independently of the main prevacuolar compartment-based trafficking route.     

The Body as Gift,Resource or Commodity? Heidegger and the Ethics of Organ Transplantation

Three metaphors appear to guide contemporary thinking about organ transplantation. Although the gift is the sanctioned metaphor for donating organs, the underlying perspective from the side of the state, authorities and the medical establishment often seems to be that the body shall rather be understood as a resource. The acute scarcity of organs, which generates a desperate demand in relation to a group of potential suppliers who are desperate to an equal extent, leads easily to the gift’s becoming, in reality, not only a resource, but also a commodity. In this paper, the claim is made that a successful explication of the gift metaphor in the case of organ transplantation and a complementary defence of the ethical primacy of the giving of organs need to be grounded in a philosophical anthropology which considers the implications of embodiment in a different and more substantial way than is generally the case in contemporary bioethics. I show that Heidegger’s phenomenology offers such an alternative, with the help of which we can understand why body parts could and, indeed, under certain circumstances, should be given to others in need, but yet are neither resources nor properties to be sold. The phenomenological exploration in question is tied to fundamental questions about what kind of relationship we have to our own bodies, as well as about what kind of relationship we have to each other as human beings sharing the same being-in-the-world as embodied creatures.