A hippocampal pyramidal neuron receives more than 10(4) excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic protein synthesis, triggered by synaptic activation of metabotropic glutamate receptors, was found to modify synaptic transmission within minutes.

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre-and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.CNS synapses are specialized sites of cell-cell contact that mediate the transmission of information between neurons. Synapses are a key site of regulation within neural networks and are characterized by multi-protein complexes arranged at tightly apposed pre-and postsynaptic terminals. Communication between neurons at synapses is mediated primarily by neurotransmitter release and by the gating of postsynaptic receptor ion channels, but a growing body of evidence indicates that signalling is also mediated by adhesion molecules that interact in a homo-or heterophilic fashion across the synaptic cleft. As at other cell-cell junctions, such as epithelial tight junctions or the immune synapse, research in a variety of neuronal subtypes has shown that synaptically localized cell adhesion molecules (SAMs) are not merely static structural components but are often dynamic regulators of synapse function. When pairs of SAMs interact, they can induce the formation of new synapses or modulate the function of existing synapses through signalling cascades or secondary protein-protein interactions. Numerous studies indicate that interactions between specific SAMs can control synapse formation, regulate dendritic spine morphology, modify synaptic receptor function and modulate synaptic plasticity. So, SAMs can mediate physical interactions between cells and act at multiple steps in the life of a synapse (FIG. 1).Here, we focus on well-studied classes of SAMs that have roles at both developing and mature synapses, namely neurexins and neuroligins, EphBs and ephrin-Bs, immunoglobulinCorrespondence to: M.B.D. dalva@mail.med.upenn.edu. Competing interests statementThe authors declare no competing financial interests. Note added in proofIn a recently published manuscript, Futai et al. 144 demonstrate that trans-synaptic β-neurexin-neuroligin interactions can modulate presynaptic function. The authors show that overexpression or knockdown of PSD-95 in the postsynaptic cell modulates presynaptic release probability, and that these effects are blocked when trans-synaptic β-neurexin-neuroligin signalling is disrupted. This paper provides further evidence that SAMs act to regulate synaptic function. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript (Ig)-containing cell adhesion molecules and cadherins. We discuss the ways in which these proteins seem to control discrete aspects of synaptic develop...

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The majority of mature excitatory synapses in the CNS are found on dendritic spines and contain AMPA-and NMDA-type glutamate receptors apposed to presynaptic specializations. EphB receptor tyrosine kinase signaling has been implicated in both NMDA-type glutamate receptor clustering and dendritic spine formation, but it remains unclear whether EphB plays a broader role in presynaptic and postsynaptic development. Here, we find that EphB2 is involved in organizing excitatory synapses through the independent activities of particular EphB2 protein domains. We demonstrate that EphB2 controls AMPA-type glutamate receptor localization through PDZ (postsynaptic density-95/Discs large/zona occludens-1) binding domain interactions and triggers presynaptic differentiation via its ephrin binding domain. Knockdown of EphB2 in dissociated neurons results in decreased functional synaptic inputs, spines, and presynaptic specializations. Mice lacking EphB1-EphB3 have reduced numbers of synapses, and defects are rescued with postnatal reexpression of EphB2 in single neurons in brain slice. These results demonstrate that EphB2 acts to control the organization of specific classes of mature glutamatergic synapses.

Most animals sleep more early in life than in adulthood, but the function of early sleep is not known. Using Drosophila, we found that increased sleep in young flies was associated with an elevated arousal threshold and resistance to sleep deprivation. Excess sleep results from decreased inhibition of a sleep-promoting region by a specific dopaminergic circuit. Experimental hyperactivation of this circuit in young flies results in sleep loss and lasting deficits in adult courtship behaviors. These deficits are accompanied by impaired development of a single olfactory glomerulus, VA1v, which normally displays extensive sleep-dependent growth after eclosion. Our results demonstrate that sleep promotes normal brain development that gives rise to an adult behavior critical for species propagation and suggest that rapidly growing regions of the brain are most susceptible to sleep perturbations early in life.

SUMMARY Motile dendritic filopodial processes are thought to be precursors of spine synapses, but how motility relates to cell-surface cues required for axon-dendrite recognition and synaptogenesis remains unclear. We demonstrate with dynamic imaging that loss of EphBs results in reduced motility of filopodia in cultured cortical neurons and brain slice. EphB knockdown and rescue experiments during different developmental time windows show that EphBs are required for synaptogenesis only when filopodia are most abundant and motile. In the context of EphB knockdown and reduced filopodia motility, independent rescue of either motility with PAK or of Ephephrin binding with an EphB2 kinase mutant is not sufficient to restore synapse formation. Strikingly, the combination of PAK and kinase-inactive EphB2 rescues synaptogenesis. Deletion of the ephrin-binding domain from EphB2 precludes rescue, indicating that both motility and trans-cellular interactions are required. Our findings provide a mechanistic link between dendritic filopodia motility and synapse differentiation.

Anti-NMDA receptor encephalitis is an autoimmune disorder in which antibodies attack NMDA (N-methyl-D-aspartate)-type glutamate receptors at central neuronal synapses. Symptoms include a highly characteristic set of neurologic deficits, but also prominent psychiatric manifestations that often bring mental health professionals into the course of care. Distinct phases of illness have become increasingly appreciated, and include a range of psychotic symptoms early in the course of the disease followed by more severe fluctuations in consciousness with neurologic involvement, and ultimately protracted cognitive and behavioral deficits. Young women are most commonly impacted and an ovarian teratoma is sometimes associated with the syndrome. Patients respond well to immunotherapy, but psychiatric symptoms can be challenging to manage. We provide an up to date review of this disorder and highlight the role of psychiatry in diagnosis, symptomatology, and treatment.

Dynamic regulation of the localization and function of N-methyl-D-aspartate receptors (NMDARs) is critical for synaptic development and function. The composition and localization of NMDAR subunits at synapses are tightly regulated, and can influence the ability of individual synapses to undergo long-lasting changes in response to stimuli. Here we examine mechanisms by which EphB2, a receptor tyrosine kinase that binds and phosphorylates NMDARs, controls NMDAR subunit localization and function at synapses. We find that in mature neurons, EphB2 expression levels regulate the amount of NMDARs at synapses, and EphB activation decreases Ca2+-dependent desensitization of NR2B-containing NMDARs. EphBs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple EphB knockout mice lacking EphB1-3 exhibit homeostatic upregulation of NMDAR surface expression and loss of proper targeting to synaptic sites. These findings demonstrate that in the mature nervous system, EphBs are key regulators of the synaptic localization of NMDARs.