Activation of silent synapses with sustained but not decremental long-term potentiation.
ABSTRACT Silent synapses display no excitatory post-synaptic currents (EPSCs) at resting potentials, but can conduct at depolarized potentials. In the hippocampal CA1 region of young animals, conversion of silent synapses to functional synapses occurs rapidly after pairing post-synaptic depolarization with 1Hz pre-synaptic stimulation, a protocol that also induces long-term potentiation (LTP). LTP appears to have a decremental phase and a sustained phase. Many studies have shown that decremental LTP can be pharmacologically isolated from sustained LTP, suggesting that they represent two distinct forms, rather than "phases" of LTP that are expressed simultaneously through different mechanisms. We investigated whether silent synapse activation (SSA) is associated specifically with the expression of sustained or decremental LTP. We found that under control conditions, in which sustained and decremental LTP were induced, SSA was observed. However, under conditions in which only decremental LTP was expressed (in the presence of a protein kinase antagonist), SSA did not occur. We conclude that SSA is associated with the expression of sustained LTP, not decremental LTP, and requires protein kinase activation. These findings support the hypothesis that decremental and sustained LTP are expressed through different mechanisms.
- SourceAvailable from: Enrico Cherubini[show abstract] [hide abstract]
ABSTRACT: Recent data indicate that most "silent" synapses in the hippocampus are "presynaptically silent" due to low transmitter release rather than "postsynaptically silent" due to "latent" receptors of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type (AMPARs). That synapses bearing only N-methyl-d-aspartate (NMDAR) receptors do exist is suggested by the decreased number of transmission failures during postsynaptic depolarisation and by the presence of NMDA-mediated excitatory postsynaptic currents (EPSCs) in synapses silent at rest. We tested whether these effects could be due to potentiated transmitter release at depolarised postsynaptic potentials rather than removal of Mg(2+) block from NMDARs. Using whole-cell recordings of minimal EPSCs from CA1 and CA3 neurones of hippocampal slices we confirmed decreased incidence of failures at +40 mV as compared with -60 mV. This effect was associated with a gradual increase of EPSC amplitude after switching to +40 mV and with a decrease of paired-pulse facilitation. In initially silent synapses, potentiation of pharmacologically isolated AMPAR-mediated EPSCs was still observed at +40 mV and this persisted after stepping back to -60 mV. All above effects were blocked when the cell was dialysed with the Ca(2+) chelator BAPTA (20 mM). These observations are difficult to reconcile with the "latent AMPAR" hypothesis and suggest an alternative explanation, namely that the reduction in failure rates at positive potentials is due to potentiation of transmitter release following Ca(2+) influx through NMDARs. Our results suggest that silent synapses can be mainly "presynaptically" rather than "postsynaptically silent" and thus increased transmitter release rather than insertion of AMPARs is a major mechanism of early long-term potentiation maintenance.Neuroscience 02/2004; 126(1):45-59. · 3.12 Impact Factor
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ABSTRACT: Despite extensive investigation, it remains unclear whether presynaptic and/or postsynaptic modifications are primarily responsible for the expression of long-term potentiation (LTP) in the CA1 region of the hippocampus. Here we address this issue by using techniques that maximize the likelihood of stimulating a single axon and thereby presumably a single synapse before and after the induction of LTP. Several basic properties of synaptic transmission were examined including the probability of neurotransmitter release (Pr), the quantal size (q), and the so-called potency, which is defined as the average size of the synaptic response when release of transmitter does occur. LTP was routinely associated with an increase in potency, whereas increases in Pr alone were not observed. LTP was also reliably induced when baseline Pr was high, indicating that synapses with high Pr can express LTP. These results suggest that the mechanism for the expression of LTP involves an increase in q and is difficult to explain by an increase in Pr alone.Proceedings of the National Academy of Sciences 09/1996; 93(16):8710-5. · 9.74 Impact Factor
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ABSTRACT: Prolonged changes in synaptic strength, such as those that occur in LTP and LTD, are thought to contribute to learning and memory processes. These complex phenomena occur in diverse brain structures and use multiple, temporally staged and spatially resolved mechanisms, such as changes in neurotransmitter release, modulation of transmitter receptors, alterations in synaptic structure, and regulation of gene expression and protein synthesis. In the CA1 region of the hippocampus, the combined activation of SRC family tyrosine kinases, protein kinase A, protein kinase C and, in particular, Ca2+/calmodulin-dependent protein kinase II results in phosphorylation of glutamate-receptor-gated ion channels and the enhancement of subsequent postsynaptic current. Crosstalk between these complex biochemical pathways can account for most characteristics of early-phase LTP in this region.Trends in Neurosciences 03/2000; · 13.58 Impact Factor