Introduction: Cell adhesion and extracellular matrix molecules in synaptic plasticity.

Abstract

This issue of Neuron Glia Biology contains a special collection of original research papers and reviews on the role of cell adhesion and extracellular matrix (ECM) molecules in synaptic plasticity. These molecules are crucially required for building and maintaining synaptic structure during brain development and there is increasing evidence that they also play important roles in modulating distinct aspects of synaptic plasticity in mature nervous system. Neuronal cell adhesion molecule (NCAM), the member of immunoglobulin family, was the first vertebrate molecule to be identified and characterized as a cell adhesion molecule. NCAM is known as the major carrier of polyanionic carbohydrate polysialic acid (PSA-NCAM) that is highly expressed during brain development, contributing to the regulation of cell shape, growth or migration. Also in adult brain, PSA-NCAM expression does persist in structures that display a high degree of plasticity, such as the hippocampus, and is involved in activity-induced synaptic plasticity. In their research manuscript Rodrı́guez et al. (2009) demonstrate that high-frequency stimulation of medial and lateral perforant path in the dentate gyrus results in NMDA-dependent homosynaptic long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) as recorded electrophysiologically in rats in vivo. This stimulation also induces increase in PSA-NCAM immunoreactivity that persists up to 24 h after stimulation. At the ultrustructural level, electron microscopy shows decreased PSA-NCAM dendritic labeling after heterosynaptic LTD and the sub-cellular relocation of PSA-NCAM to the spines after homosynaptic LTP, that are independent of NMDA receptor activation. These findings suggest that strong activation of the granule cells in dentate gyrus up-regulates PSA-NCAM synthesis in the cell body, with subsequent transport to the dendrite and incorporation into activated synapses, representing NMDA-independent plastic processes that may act synergistically with LTP/LTD mechanisms. The review by Dityatev et al. (2009) summarizes the roles of cell adhesion molecules of the immunoglobulin superfamily (Ig-CAMs) and semaphorins (some of which also contain Ig-like domains) in regulation of synaptic transmission and plasticity at multiple subtypes of excitatory synapses in the hippocampus. The Ig-CAMs discussed in this review, including NCAM, L1, CHL1, neuroplastin, Thy-1, contactin-1 and semaphorins, belong to distinct subfamilies. Interestingly, among Ig-CAMs, only NCAM proved to be important for all tested forms of hippocampal plasticity. The emerging mechanisms by which adhesive Ig-CAMs contribute to synaptic plasticity involve regulation of activities of NMDA receptors and L-type Ca2þ channels, signaling via mitogenactivated protein kinase p38, changes in GABAergic inhibition and motility of synaptic elements. Regarding repellent molecules, available data for semaphorins demonstrate their activity-dependent regulation in normal and pathological conditions, synaptic localization of their receptors and their potential to elevate or inhibit synaptic transmission either directly or indirectly. Integrin receptors represent another class of recognition molecules that mediate adhesion of the cell to the ECM and thereby regulate cell motility, proliferation, differentiation and apoptosis, as well as stabilize activity-induced increases in synaptic strength and excitability. In this special issue Cingolani and Goda (2009) further examine the role of b3 in homeostatic plasticity in organotypic slices, and ask if homeostatic plasticity may function differently between dissociated cultured neurons and organotypic slices. Using electrophysiological recordings in dissociated culture and organotypic slices prepared from b3 integrin knockout mice, several forms of homeostatic synaptic regulation are investigated. Results of this study demonstrate that b3 integrin is specifically required for a postsynaptic form of synaptic homeostasis called synaptic scaling in both dissociated cultures and organotypic slices. Another form of synaptic homeostasis that involves changes in presynaptic quantal content occurs independently of b3 integrin. This study shows that homeostatic synaptic plasticity induced by chronic TTX treatment is partially mechanistically different between primary cultures and organotypic slice cultures, indicating that mechanisms for homeostatic regulation in native brain may be distinct from those in neuronal culture preparation. Receptor tyrosine kinases (RTKs) are cell surface molecules implicated in a variety of neuronal functions, including neuronal survival, axon and dendrite outgrowth, and synapse development. Two families of RTKs, ErbBs and Ephs, exhibit similar characteristics in their bi-directional signaling transduction. The forward and reverse signaling of ErbBs and Ephs have been implicated in various aspects of synapse development, including dendritic spine morphogenesis, synapse formation, maintenance and plasticity. Chen et al. (2009) in their review discuss the latest advances in the functions of ErbBs and Ephs, as well as their ligands neuregulins (NRG) and ephrins, at the synapse, including dendritic spine morphogenesis, synapse formation and maturation. Regulated trans-synaptic interaction between RTKs receptors and their ligands is essential for synaptic transmission and plasticity. In addition to signaling at excitatory glutamatergic and inhibitory GABAergic synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions and is mediated by NRG/ErbB and ephrin/Eph signaling. Implications of signaling events, mediated by RTKs and their cognate ligands, in human diseases is also discussed. The importance of proteolytic activity regulation at or near the synapses, or perisynaptic proteolysis, as one of the mechanisms underlying synaptic plasticity is discussed in the review by Lee et al. (2009). It has been demonstrated that perisynaptic release and/or activation of various proteases is dependent on neuronal activity. This is followed by cleavage