Synapse regulation exploits the capacity of actin to function as a stable structural component or as a dynamic filament. Beyond its well-appreciated role in eliciting visible morphological changes at the synapse, the emerging picture points to an active contribution of actin to the modulation of the efficacy of pre- and postsynaptic terminals. Moreover, by engaging distinct pools of actin and divergent signalling pathways, actin-dependent morphological plasticity could be uncoupled from modulation of synaptic strength. The aim of this Review is to highlight some of the recent progress in elucidating the role of the actin cytoskeleton in synaptic function.

At synapses, cell adhesion molecules (CAMs) provide the molecular framework for coordinating signaling events across the synaptic cleft. Among synaptic CAMs, the integrins, receptors for extracellular matrix proteins and counterreceptors on adjacent cells, are implicated in synapse maturation and plasticity and memory formation. However, little is known about the molecular mechanisms of integrin action at central synapses. Here, we report that postsynaptic beta3 integrins control synaptic strength by regulating AMPA receptors (AMPARs) in a subunit-specific manner. Pharmacological perturbation targeting beta3 integrins promotes endocytosis of GluR2-containing AMPARs via Rap1 signaling, and expression of beta3 integrins produces robust changes in the abundance and composition of synaptic AMPARs without affecting dendritic spine structure. Importantly, homeostatic synaptic scaling induced by activity deprivation elevates surface expression of beta3 integrins, and in turn, beta3 integrins are required for synaptic scaling. Our findings demonstrate a key role for integrins in the feedback regulation of excitatory synaptic strength.

In most central neurons, action potentials are followed by an afterhyperpolarization (AHP) that controls firing pattern and excitability. The medium and slow components of the AHP have been ascribed to the activation of small conductance Ca 2؉ -activated potassium (SK) channels. Cloned SK channels are heteromeric complexes of SK ␣-subunits and calmodulin. The channels are activated by Ca 2؉ binding to calmodulin that induces conformational changes resulting in channel opening, and channel deactivation is the reverse process brought about by dissociation of Ca 2؉ from calmodulin. Here we show that SK channel gating is effectively modulated by 1-ethyl-2-benzimidazolinone (EBIO). Application of EBIO to cloned SK channels shifts the Ca 2؉ concentration-response relation into the lower nanomolar range and slows channel deactivation by almost 10-fold. In hippocampal CA1 neurons, EBIO increased both the medium and slow AHP, strongly reducing electrical activity. Moreover, EBIO suppressed the hyperexcitability induced by low Mg 2؉ in cultured cortical neurons. These results underscore the importance of SK channels for shaping the electrical response patterns of central neurons and suggest that modulating SK channel gating is a potent mechanism for controlling excitability in the central nervous system.

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SummaryMutations in TSPAN7—a member of the tetraspanin protein superfamily—are implicated in some forms of X-linked intellectual disability. Here we show that TSPAN7 overexpression promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats, whereas TSPAN7 silencing reduces head size and stability of spines and AMPA receptor currents. Via its C terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking. These findings indicate that, in hippocampal neurons, TSPAN7 regulates AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability.

Calcium transients play an important role in the early and later phases of differentiation and maturation of single neurons and neuronal networks. Small-conductance calcium-activated potassium channels of the SK type modulate membrane excitability and are important determinants of the firing properties of central neurons. Increases in the intracellular calcium concentration activate SK channels, leading to a hyperpolarization of the membrane potential, which in turn reduces the calcium inflow into the cell. This feedback mechanism is ideally suited to regulate the spatiotemporal occurrence of calcium transients. However, the role of SK channels in neuronal development has not been addressed so far. We have concentrated on the ontogenesis and function of SK channels in the developing rat cerebellum, focusing particularly on Purkinje neurons. Electrophysiological recordings combined with specific pharmacological tools have revealed for the first time the presence of an afterhyperpolarizing current (I(AHP)) in immature Purkinje cells in rat cerebellar slices. The channel subunits underlying this current were identified as SK2 and localized by in situ hybridization and subunit-specific antibodies. Their expression level was shown to be high at birth and subsequently to decline during the first 3 weeks of postnatal life, both at the mRNA and protein levels. This developmental regulation was tightly correlated with the expression of I(AHP) and the prominent role of SK2 channels in shaping the spontaneous firing pattern in young, but not in adult, Purkinje neurons. These results provide the first evidence of the developmental regulation and function of SK channels in central neurons.

The precise contribution of the cadherin-␤-catenin synapse adhesion complex in the functional and structural changes associated with the pre-and postsynaptic terminals remains unclear. Here we report a requirement for endogenous ␤-catenin in regulating synaptic strength and dendritic spine morphology in cultured hippocampal pyramidal neurons. Ablating ␤-catenin after the initiation of synaptogenesis in the postsynaptic neuron reduces the amplitude of spontaneous excitatory synaptic responses without a concurrent change in their frequency and synapse density. The normal glutamatergic synaptic response is maintained by postsynaptic ␤-catenin in a cadherin-dependent manner and requires the C-terminal PDZ-binding motif of ␤-catenin but not the link to the actin cytoskeleton. In addition, ablating ␤-catenin in postsynaptic neurons accompanies a block of bidirectional quantal scaling of glutamatergic responses induced by chronic activity manipulation. In older cultures at a time when neurons have abundant dendritic spines, neurons ablated for ␤-catenin show thin, elongated spines and reduced proportion of mushroom spines without a change in spine density. Collectively, these findings suggest that the cadherin-␤-catenin complex is an integral component of synaptic strength regulation and plays a basic role in coupling synapse function and spine morphology.␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors ͉ spine morphology ͉ synapse adhesion proteins ͉ quantal scaling S ynaptic plasticity is a major means by which neuronal networks adapt to experience. Recent studies suggest that synapses also undergo activity-dependent structural remodeling that might subserve functional synaptic changes (1, 2). Stimulus protocols that induce durable forms of long-term potentiation produce a transient rise in the number of perforated synapses (3, 4) and axonal varicosities (5) and trigger the reorganization of the synaptic actin cytoskeleton to form new functional boutons (6). Dendritic spines also undergo stimulus-dependent active remodeling (7) by mechanisms that involve actin dynamics (8-10). Because the apposition of the presynaptic active zone and the postsynaptic density is always closely matched, remodeling of either the active zone or the dendritic spine must, at some point, accompany a parallel change in the opposite membrane specialization. How the two sides of the synaptic terminals undergo coordinated changes, however, remains to be established.Several cell adhesion proteins have been identified at synapses where they are implicated in forming and/or maintaining synaptic junctions (11,12). The best studied among such proteins are the classical cadherins, homophilic Ca 2ϩ -dependent adhesion molecules, which also play a role in axon outgrowth (13,14), dendrite arborization (15), and target recognition (16). Whereas the extracellular domain of cadherins provides the direct intercellular link between apposing cells, strong adhesion by cadherins requires the dynamic intracellular connection to the actin cyt...

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