Changes in synaptic structure underlie the developmental speeding of AMPA receptor–mediated EPSCs

Cathala, Laurence; Holderith, Noémi; Nusser, Zoltán; DiGregorio, David A.; Cull-Candy, SG

doi:10.1038/nn1534

Cited by 112 publications

(121 citation statements)

References 48 publications

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“…Similarly, the number of glutamate molecules released into the cleft was varied from the baseline value of 3,000 (35) to 8,000, to reflect the possibility of multivesicular release at this synaptic type (36). Finally, the lateral size of the synaptic apposition was varied 5-fold (between 200 and 1,000 nm), to reflect the high variability, including age-dependence, of the overall synaptic dimensions (10)(11)(12)19). Within this range of synaptic parameters, the theoretical calculations described above predict that the maximum amplitude of synaptic current I syn peaks when ␦ falls between Ϸ10 and 20 nm (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In turn, increasing the lateral cleft size could generally slow down neurotransmitter escape from the cleft and thus prolong synaptic responses (9). Indeed, faster AMPA receptor-mediated EPSCs have recently been associated with smaller synaptic apposition zones in the developing cerebellar synapses (10). However, lateral dimensions of synapses fluctuate considerably (even within homogeneous synaptic populations), whereas the cleft height remains remarkably stable.…”

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confidence: 99%

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The optimal height of the synaptic cleft

Savtchenko

Rusakov

2007

Proc. Natl. Acad. Sci. U.S.A.

148

181

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Signal integration in the brain is determined by the size and kinetics of rapid synaptic responses. The latter, in turn, depends on the concentration profile of neurotransmitter in the synaptic cleft. According to a traditional view, narrower clefts should correspond to higher intracleft concentrations of neurotransmitter, and therefore to the enhanced activation of synaptic receptors. Here, we argue that narrowing the cleft also increases electrical resistance of the intracleft medium and therefore reduces local receptor currents. We employ detailed theoretical analyses and Monte Carlo simulations to propose that these two contrasting phenomena result in a relatively narrow range of cleft heights at which the synaptic receptor current reaches its maximum. Over a physiological range of synaptic parameters, the ''optimum'' height falls between Ϸ12 and 20 nm. This range is consistent with the structure of central synapses reported by electron microscopy. Therefore, our results suggest that a simple fundamental principle may underlie the synaptic cleft architecture: to maximize synaptic strength.T he waveform of rapid synaptic responses shapes the temporal domain of signal integration in the brain (1, 2). In turn, the kinetics of synaptic receptor currents is constrained by diffusion of neurotransmitter in the synaptic cleft (3, 4). This relationship, however, remains poorly understood, mainly because events inside the cleft are beyond the powers of direct experimental observation. There is little doubt, however, that synaptic cleft geometry is an important factor in shaping synaptic currents (3, 5-7). The straightforward logic of physics predicts that decreasing the cleft height should increase the intracleft concentration of neurotransmitter and therefore enhance activation of synaptic receptors (8). In turn, increasing the lateral cleft size could generally slow down neurotransmitter escape from the cleft and thus prolong synaptic responses (9). Indeed, faster AMPA receptor-mediated EPSCs have recently been associated with smaller synaptic apposition zones in the developing cerebellar synapses (10). However, lateral dimensions of synapses fluctuate considerably (even within homogeneous synaptic populations), whereas the cleft height remains remarkably stable. For instance, at the common excitatory synapses in hippocampal area CA1, the lateral cleft area varies several-fold (11) whereas the cleft height shows the coefficient of variation (an upper estimate) of only Ϸ26% (12). Interestingly, osmotic challenge or other physiological manipulations that affect dramatically the overall extracellular space dimensions (13, 14) do not appear to modify the synaptic cleft height (15). This parameter also remains virtually unchanged during development (16-18). Remarkably, in electron micrographs of synaptosomes (a preparation obtained using strong mechanical forces of centrifugal separation), the distance between the apposing synaptic membranes is indistinguishable from that in the intact neuropil. Across many synaptic type...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The optimal height of the synaptic cleft

Savtchenko

Rusakov

2007

Proc. Natl. Acad. Sci. U.S.A.

148

181

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“…2C). The slowed time course of mEPSCs could reflect changes in the synaptic structure or organization, including the composition of AMPAR subunits (30,31).…”

Section: Loss Of Endogenous ␤-Catenin Produces Subtle Changes In Synapsementioning

confidence: 99%

β-Catenin regulates excitatory postsynaptic strength at hippocampal synapses

Okuda

Cingolani

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

113

109

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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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“…However, the functional impact of synaptic currents depends not only on amplitude but also on the timecourse. In particular, synaptic current duration (typically assessed as the weighted decay time constant) can strongly affect synaptic integration and this parameter is known to undergo a developmental increase that is strictly correlated with alterations in synapse geometry (Cathala et al, 2005;Wall et al, 2002). Treatment of neurons with MMP-9, MMP-9 E402A or buffer had no significant effect on the mEPSC decay time course in neurons treated for 30 or 60 minutes (data not shown).…”

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confidence: 97%

Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology

Michaluk

Wawrzyniak

Alot

et al. 2011

Journal of Cell Science

194

187

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SummaryAn increasing body of data has shown that matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn 2+ -dependent endopeptidase, is important not only for pathologies of the central nervous system but also for neuronal plasticity. Here, we use three independent experimental models to show that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal neurons. These models are: a recently developed transgenic rat overexpressing autoactivating MMP-9, dissociated neuronal cultures, and organotypic neuronal cultures treated with recombinant autoactivating MMP-9. This dendritic effect is mediated by integrin b1 signalling. MMP-9 treatment also produces a change in the decay time of miniature synaptic currents; however, it does not change the abundance and localization of synaptic markers in dendritic protrusions. Our results, considered together with several recent studies, strongly imply that MMP-9 is functionally involved in synaptic remodelling.

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Changes in synaptic structure underlie the developmental speeding of AMPA receptor–mediated EPSCs

Cited by 112 publications

References 48 publications

The optimal height of the synaptic cleft

The optimal height of the synaptic cleft

β-Catenin regulates excitatory postsynaptic strength at hippocampal synapses

Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology

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