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Integrins are a family of heterodimeric cell adhesion molecules (CAMs), whose α and β subunits are noncovalently united. By executing cell-cell, cell-matrix and cell- pathogen interactions, they are implicated to be pivotal for development, immunopathogenesis and signalling transduction . Here we focus on integrin subtypes expressed in central nervous system (CNS), draw attention on the receptor-ligand signalling mechanisms in modulating synaptic scaling, and discuss how integrins regulate synaptic strength in activity-dependent neuronal functions, which is supposed to be the underlying mechanism of memory storage and retrieval. Finally we preview future detailed illustration of integrin as significant modifiers in homeostatic neuronal network.
Structure and adhesion dynamics of integrin
Integrins are α and β heterodimers with each subunits cross membrane once. Most polypeptides are extracellular and only two short cytoplasmic domains are intracellular. Composed by two subunits with combinations, the mammalian integrins seem to have evolved for different roles. As a transmembrane protein, integrin communicates extracellular matrix (ECM) with intracellular cytoskeleton to send or receive signals. With the ability of responding to bind many signal transduction pathway proteins, integrin can activate, deactivate or regulate downstream molecules in multiple physiological processes . To understand integrin as synaptic mechanical stabilizer we should know the structural coordination of integrin linking ECM and cytoskeleton. During cell migration, integrin is activated to cluster and form focal adhesion, during which the integrin links actin cytoskeleton and ECM. Integrin density is higher in sliding parts of the cell while in the cell front is stationary, and this higher density involves a fast integrin β3 turnover. Clustered integrins requires complex formation consisting of integrin, ligands, talin and PI(4,5)P2 lipid to dynamically remodel, which may also suggested a possible mechanism in the nervous system .
Integrins in the CNS as functional regulators as other CAMs
Strong evidences confirmed most CAMs not only as structural components of cell membrane, but also crucial roles in the synaptic formation, dendritic spine morphology and synaptic plasticity . Among which Cadherin, Ephrin and Eph, Neurexin and Neuroligin showed great significance in mediating synaptic functions. For instance, in synaptogenesis the interaction of presynaptic Neurexin and postsynaptic Neuroligin, both could undergo alternative splicing to produce thousands of specific connections to determine synapse contact. In vivo and in vitro experimental results showed Neuroexin-Neuroligin interactions in controlling synapse formation and specification . Relatively, Neuroexin also regulates presynaptic calcium channel function . Ephrins have been of dominance for adult neurogenesis and Eph-Ephrin interactions for axon guidance or dendritic spine morphogenesis . In special, postsynaptic EphB has several domains enabling its bidirectional signalling functions in many parts controlling synaptogenesis both in vivo and in vitro . Ephs and Ephrins modulate synaptic plasticity by mediating glutamate receptor NMDAR dependent synaptic plasticity in Mossy fibre-CA3 and Schaeffer collateral-CA1 hippocampal synapses, but the underlying mechanism remains poor known . Cadherin as another family of CAMs, are widely expressed at pre- and postsynaptic terminals. N-Cadherin can bind to β-catenin and then connect to actin cytoskeleton, together stabilize the synaptic morphology in basal conditions or network activities. Cadherins are also shown to be involved in multiple synaptic dynamics like presynaptic function, short-term plasticity and long-term potentiation (LTP) . N-Cadherin-β-catenin complex can also regulate AMPAR trafficking, which is a major form of synaptic strength changes .
Together these CAMs are highlighted for important players in synaptic development and function. However, integrins have received little consideration regardless of many subtypes of integrins exist in the CNS, mainly αVβ3 and β1 integrins, which are widely expressed in the neurons and especially in the synapses . Past studies have partly elucidated integrin could influence synaptic function. Overexpression or loss of integrin leads to synaptic efficacy changes, thus modulate NMDAR mediated synaptic currents related to LTP, but the structural mechanism is unknown ; In the Drosophila Volado mutant ceased integrin expression would eliminate short-term olfactory . More recently, spine remodelling is found to be connected with ECM-integrin activities, and β1 integrin mutants would cause working memory, spatial memory and LTP deficits, also linked integrin signalling with AMPA receptor integrities .
Synaptic homeostasis is associated with integrin trans-synaptic modulation
Synapses innervate a kind of homeostasis in the neuronal network in which the synapses in one neuron respond specifically to the network activities by changing their connectivity or synaptic strength. This finding could explain many phenomena like memory storage, forgetting and even neuronal disorders . Concerning integrin, especially its expression in pre- and postsynaptic terminals, it is of interest to investigate the exact participating form of different integrin subtypes during homeostatic synaptic scaling. Goda group used multiple approaches to understand how pre- and postsynaptic integrins act to modulate synaptic strength, and the underlying molecular mechanisms . In dissociated culture neurons, by destroying integrin-ligand binding with echistatin, they found a decrease in mEPSC amplitude, with Ca2+ going in through NMDAR needed. This decrease is companied by an increase in AMPAR GluR2 subunit endocytosis requiring Rap1 activation and reduced AMPAR currents. Since Rap1 signalling is associated with integrin, this kind of integrin-blocked homeostatic model would be that disrupted integrin signalling would activate Rap1 to increase GluR2 endocytosis, causing AMPAR current reduced. For another model, action potential blockade by TTX treatment would induce extracellular TNFα, which upregulates β3 integrin expression and stabilize GluR2 containing AMPAR. Actually there are many kinds of homeostatic plasticity, and the integrin regulating network in the synapse is far more complex than we imagine.
In a most recent study they prepared both dissociated cultures and organotypic slices to compare the differences of pre- and postsynaptic integrins in different synaptic homeostasis, revealing a complex division of integrin action . Organotypic slices seems much more mimic of in vivo facts, with neurons react differently to inputs while for dissociated cultures lacking such discrimination is evident. The results showed that in organotypic slices activity deprivation would increase presynaptic quantal content and postsynaptic quantal size, but without integrin β3 postsynaptic quantal size could not change, showing that presynaptic modification is independent of integrin β3; however in dissociated cultures, activity deprivation increased quantal size only, and without integrin β3 everything remained unchanged, which is largely because of the difference of integrin β3 dysfunction conditions.
Studies of integrins as key element in synaptic function are most conducted in excitatory neurons, with very few reports in the inhibitory synapses. A most recent literature spotlighted a cross-talk mechanism of integrin β3 and β1via CaMK II regulates inhibitory GlyR trapping and gephrin trafficking . Concerning the integrin β1 function in LTP targeting NMDA receptor, it is promising to conduct research in both excitatory and inhibitory synapses, as well as single integrin subtype and mutual interactions.
Trans-synaptic integrin signalling
Consistent with the previous experimental results, integrin β3 is responsible for synaptic scaling during network changes only at the postsynaptic level; however data from dissociated cultures and integrin expression patterns in the synapses suggest there may be other integrin subtypes compensate for the scaling process. In that many candidates could be selected for future experimental design.
To modulate the synaptic strength onto homeostasis integrin can enhance both presynaptic quantal content by enhancing neurotransmitter release efficacy, and increase postsynaptic quantal size by stabilizing the AMPA receptor. So how integrin as cell adhesion molecule send information to the presynaptic terminal to regulate? Integrin as transmembrane protein could link ECM and actin; actin is present at presynaptic terminals and via actin-synapsin-vesicles to dynamically mobilize the vesicle pool ; actin remodelling requiring Rho family of small GTPases is implicated in synapse formation, and actin has been reported significant for the clustering of the reserve synaptic vesicle pool, the delivering of synaptic vesicles to the active zone and synaptic vesicle exocytosis . Present of these findings the integrin and actin cytoskeleton coordination in a trans-synaptic manner would answer how synaptic scaling is fine tuned. One potential key factor is talin, forming the focal adhesions of cells and ECM, and bind to the integrin, is an adaptor between integrin and actin cytoskeleton. Talin binds with F-actin, and can bind to β3 integrin binding site at its F3, and talin activation needs the participation of Rap1 . Besides, talin is recently found to be present at neuron, but its function remains unknown. Previous studies revealed a key role of talin, that after talin dysfunction through PIP kinase interruption, the actin dynamics and synaptic vesicle endocytosis are severely perturbed . Undoubtedly, talin is probably to be a key modulator in trans-synaptic signalling pathway.
Past decades we have witnessed exciting discoveries of the homeostatic synaptic plasticity and its increasing significance to be found in adult neurogenesis, memory storage and retrieval, neuronal network dynamics and brain disorders. Nevertheless, we still know little about the molecular and cellular mechanisms of this plasticity. How network signals are transformed to single cells? How signalling pathway works to produce physiological and morphological changes? During adult neurogenesis and new memory formation, how the homeostasis breaks and rebalances? In neuronal death, what the homeostasis accounts for?
With techniques progress, we have been able to use multiple culture methods and imaging facilities, as well as single-molecule fluorescence and optogenetics to reveal the neuronal activity real time. It is promising that the whole signalling of synaptic scaling would become clear for better understand the brain working theory.