Differential induction of LTP and LTD is not determined solely by instantaneous calcium concentration: an essential involvement of a temporal factor

Abstract

Two opposite types of synaptic plasticity in the CA1 hippocampus, long-term potentiation (LTP) and long-term depression (LTD), require postsynaptic Ca2+ elevation. To explain these apparently contradictory phenomena, the current view assumes that a moderate postsynaptic increase in Ca2+ leads to LTD, whereas a large increase leads to LTP. No detailed study has so far been attempted to investigate whether the instantaneous Ca2+ elevation level differentially induces LTP or LTD. We therefore used low-frequency (1 Hz) stimulation of Schaffer collateral/commissural fibers in rat hippocampal slices, during a Mg2+-free period, as the conditioning stimulus to investigate this. This allowed low-frequency afferent stimulation to cause a postsynaptic Ca2+ influx because the voltage-dependent block of N-methyl-D-aspartate (NMDA) receptor-channels by Mg2+ was removed. When delivered during the Mg2+-free period, a single pulse, as well as 2-600 pulses, induced LTP that was occluded with tetanus-induced LTP. To decrease the Ca2+ influx, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were completely blocked by the addition of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to the conditioning medium, in which 1 Hz afferent stimuli (1-600 pulses) induced less LTP and never induced LTD. To further reduce the Ca2+ influx, NMDA receptors were partially blocked with D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5). A small number of 1 Hz stimuli, however, never induced LTD. Only when the conditioning stimuli exceeded 200 pulses was LTD induced. The present findings provide definitive evidence that protracted conditioning is a prerequisite for the induction of LTD. Thus, not only the amplitude but also the duration of postsynaptic Ca2+ elevation could be essential factors for differentially inducing LTP or LTD.

Malleability of Spike-Timing-Dependent Plasticity at the CA3-CA1 Synapse

“…A striking feature in protocols leading to LTD is that depression often requires activity for a longer period of time than potentiation (Dudek and Bear, 1992;Yang et al, 1999;Mizuno et al, 2001;O'Connor et al, 2005b). In addition, causal STDP protocols can lead to depression (Christie et al, 1996) but not if the number of presynaptic and postsynaptic action potential pairings is small (Pike et al, 1999;Meredith et al, 2003).…”

Invited Review: Neuroplasticity in respiratory motor control

“…Important variables include the duration, intensity, pattern, and history of stimulation. The duration and intensity of stimulation often determine the duration and direction (potentiation vs. depression) of the resulting plasticity (36,168). Important forms of synaptic plasticity are elicited preferentially by intermittent vs. sustained stimuli.…”

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).…”

“…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].…”

“…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].…”