Selective Induction of LTP and LTD by Postsynaptic [Ca²⁺]_i Elevation

Abstract

Long-term potentiation (LTP) and long-term depression (LTD), two prominent forms of synaptic plasticity at glutamatergic afferents to CA1 hippocampal pyramidal cells, are both triggered by the elevation of postsynaptic intracellular calcium concentration ([Ca2+]i). To understand how one signaling molecule can be responsible for triggering two opposing forms of synaptic modulation, different postsynaptic [Ca2+]i elevation patterns were generated by a new caged calcium compound nitrophenyl-ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid in CA1 pyramidal cells. We found that specific patterns of [Ca2+]i elevation selectively activate LTP or LTD. In particular, only LTP was triggered by a brief increase of [Ca2+]i with relatively high magnitude, which mimics the [Ca2+]i rise during electrical stimulation typically used to induce LTP. In contrast, a prolonged modest rise of [Ca2+]i reliably induced LTD. An important implication of the results is that both the amplitude and the duration of an intracellular chemical signal can carry significant biological information.

Calcium control of triphasic hippocampal STDP

“…Hill co-efficients and dissociation constants are set in line with previous experimental and theoretical studies, and the empirically observed competition between these two pathways is accounted for by dictating that kinase activity partially inhibits phosphotase activity [40,41,44,49,50]. Finally, the activation of kinase and phosphotase must also obey different kinetics, such that LTP can be induced rapidly, by a small number of triplet pairings, while significant LTD requires more sustained stimulation [15,17,29]. This is achieved by assigning a much more rapid time constant of decay to the kinase pathway compared to the phosphotase pathway (50ms and 2000ms respectively).…”

“…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]. Computational modelling of synaptic plasticity has demonstrated that the dynamics of Calcium influx through the NMDA receptor (NMDAr) is sufficient to account for empirical data obtained using multiple stimulation protocols, integrating an array of experimental results within a single theoretical framework [18,[41][42][43][44][45][46][47][48].…”

“…In spite of the heterogeneity of plasticity mechanisms observed throughout the brain, changes in the strength of excitatory synapses afferent on CA1 pyramidal neurons in the hippocampus represent the best studied form in the mammalian cortex [9][10][11][12]. At these synapses, Calcium influx into dendritic spines represents the critical signal for synaptic plasticity induction [13][14][15][16][17][18][19][20]. Large, transient elevations in intracellular [Ca 2+ ] generate LTP via the preferential activation of kinase pathways while modest, sustained elevations in intracellular [Ca 2+ ] generate LTD via the preferential activation of phosphotase pathways [21][22][23][24][25].…”

Complexity of calcium signaling in synaptic spines

“…(16,27,28) The spine can therefore be treated as a single compartment with respect to [Ca 2þ ] i under these conditions; ignoring gradients induced by the spatial localization of Ca 2þ pumps and exchangers on membrane surfaces. However, the spine cannot be considered a single calcium compartment for normal physiological stimuli.…”

“…(17) Furthermore, genetic manipulation of the NMDAR subunit composition resulting in an increase in the amount of Ca 2þ entering the cell results in LTP induction at lower stimulation frequencies. (25) Fifth, direct manipulation of postsynaptic Ca 2þ levels using diffuse photolytic uncaging of chelated Ca 2þ is sufficient to induce both LTP and LTD. (16,(26)(27)(28) Specifically, large ($10 mM), brief ($3 sec) increases in [Ca 2þ ] i reliably induce LTP, whereas a modest ($0.7 mM), long ($60 sec) increases in [Ca 2þ ] i reliably induce LTD. (28) Spike-timing-dependent plasticity The temporal order of pre-and postsynaptic activation may also be important for the selective induction of LTP and LTD. (7,29) With the finding that an action potential, or spike, induced by a current injection into the soma, not only travels down the axon but also propagates back through the dendrites, (30) the timing of the presynaptic input (the release of glutamate) and the postsynaptic output (the spike) can be controlled with millisecond precision. A fascinating picture has since emerged.…”