Long-term potentiation of exogenous glutamate responses at single dendritic spines

Abstract

Long-term increases in the strength of excitatory transmission at Schaffer collateral-CA1 cell synapses of the hippocampus require the insertion of new ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) into the synapse, but the kinetics of this process are not well established. Using microphotolysis of caged glutamate to activate receptors at single dendritic spines in hippocampal CA1 cells, we report the long-lasting potentiation of AMPAR-mediated currents with only a single pairing of photoreleased glutamate and brief postsynaptic depolarization. This potentiation was N-methyl-D-aspartate receptor (NMDAR)-dependent and was reversed with low-frequency photostimulation in an NMDAR-dependent manner, suggesting that it is mediated by the same mechanism(s) as conventional synaptic long-term potentiation. Potentiation of photolytic responses developed rapidly in a stepwise manner after a brief and variable delay (<60 s) at spines, but could not be induced at extrasynaptic sites on the dendritic shaft. Potentiation was accompanied by a concomitant decrease in postsynaptic, polyamine-dependent paired-pulse facilitation of the photolytic currents, indicating that a change in the subunit composition of the AMPARs underlying the response contributed to the potentiation. These changes are consistent with an increase in the proportion of GluR2-containing AMPARs in the spine head. These results demonstrate that activation of postsynaptic glutamate receptors by glutamate is not only necessary, but sufficient, for the induction of NMDAR-dependent long-term potentiation and reveal additional aspects of its expression.synaptic plasticity ͉ hippocampus ͉ plasticity L ong-term plasticity of excitatory synaptic transmission that depends on N-methyl-D-aspartate receptor (NMDAR) activation is likely to underlie learning and memory formation (1, 2). Despite an abundance of knowledge about long-term potentiation (LTP), considerable uncertainty and controversy about the mechanisms of LTP induction and expression persist. Some of these controversies are likely to stem from the use of conventional synaptic stimulation for studying LTP because the presynaptic nerve terminal is an unreliable source of glutamate. For example, several previous attempts to induce LTP with exogenous glutamate have not been successful (3, 4), raising the possibility that there is a factor other than glutamate that is coreleased from nerve terminals with synaptic stimulation and is required for LTP induction. Likewise, changes in paired-pulse ratio (PPR) have been reported to accompany LTP in some studies and have been interpreted as evidence of a change in presynaptic release probability (5, 6). Matsuzaki et al. (7) have demonstrated that potentiation of glutamate responses can be achieved with repeated photorelease from caged glutamate targeted to dendritic spines, suggesting that activation of synaptic glutamate receptors is critical.The ability to study LTP with exogenous glutamate offers a powerful tool for answering fundamental questions...

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

“…It is possible that translocation of perisynaptic AMPARs and subunit switch occur very rapidly with pairing protocol and that these processes were already completed by the time PhTx433 was added (20). This scenario is consistent with more GluR2-containing AMPARs being present after LTP induction (42). An alternative scenario is that different induction protocols leads to two different forms of LTP, one that requires GluR2-lacking AMPARs and another that does not.…”

Calcium control of triphasic hippocampal STDP

“…Similar results have been obtained at excitatory connections between cortical pyramidal neurons [35]. Other experimental data indicates that potentiation and depression events are switch-like transitions between binary conductance states, mediated by kinase and phosphotase pathways that are co-activated and competitive [36][37][38][39][40]. The kinetics of kinase and phosphotase activation also differ significantly, as LTP can be rapidly induced by appropriate patterns of activity while LTD requires prolonged stimulation [15,17,29].…”

“…It is also interesting to note that, due to the higher gain and shorter time constant governing kinase activation, transitions between low and high weight states induced by potentiating stimuli take consistently less time than transitions between high and low weight states induced by depressing stimuli (69±50s at ∆t=15ms and 108±55s at ∆t=-15ms for 5Hz Triplet pairing, for example), and each is on a similar timescale to that observed experimentally (80±70s for LTP and 183±126s for LTD in O'Connor, Wittenberg and Wang [37]; 38s for LTP in Bagal et al [39]). …”

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

“…Previous studies that assess receptor movement biochemically or using epitope-tagged receptors have indicated that GluR1-containing AMPARs are delivered to extrasynaptic sites (31,32,34), and extrasynaptic AMPARs can be activated using exogenous agonists (47,48). However, our study defines the trafficking of native AMPARs around the perisynaptic region in response to activity-dependent LTP.…”