IP₃ mobilization and diffusion determine the timing window of Ca²⁺ release by synaptic stimulation and a spike in rat CA1 pyramidal cells

Abstract

Synaptically activated calcium release from internal stores in CA1 pyramidal neurons is generated via metabotropic glutamate receptors by mobilizing IP3. Ca2+ release spreads as a large amplitude wave in a restricted region of the apical dendrites of these cells. These Ca2+ waves have been shown to induce certain forms of synaptic potentiation and have been hypothesized to affect other forms of plasticity. Pairing a single backpropagating action potential (bAP) with repetitive synaptic stimulation evokes Ca2+ release when synaptic stimulation alone is subthreshold for generating release. We examined the timing window for this synergistic effect under conditions favoring Ca2+ release. The window, measured from the end of the train, lasted 250–500 ms depending on the duration of stimulation tetanus. The window appears to correspond to the time when both IP3 concentration and [Ca2+]i are elevated at the site of the IP3 receptor. Detailed analysis of the mechanisms determining the duration of the window, including experiments using different forms of caged IP3 instead of synaptic stimulation, suggest that the most significant processes are the time for IP3 to diffuse away from the site of generation and the time course of IP3 production initiated by activation of mGluRs. IP3 breakdown, desensitization of the IP3 receptor, and the kinetics of IP3 unbinding from the receptor may affect the duration of the window but are less significant. The timing window is short but does not appear to be short enough to suggest that this form of coincidence detection contributes to conventional spike timing-dependent synaptic plasticity in these cells.

Understanding calcium waves and sparks in central neurons

“…Once CICR is initiated, regenerative propagation will continue provided that IP 3 is available; the level of IP 3 at rest is not sufficient. The requirement for co-activation by IP 3 and Ca 2+ makes regenerative Ca 2+ release a coincidence detector for metabotropic glutamate receptor (mGluR) or muscarinic acetylcho-line receptor (mAChR) activation (which mobilizes IP 3 ) and postsynaptic Ca 2+ signalling (from bAPs or dendritic Ca 2+ spikes) in pyramidal neurons 17,22,38 and Purkinje neurons 39 . The timing window for this synergistic response varies from 100 to 500 ms 17,38,39 .…”

“…The requirement for co-activation by IP 3 and Ca 2+ makes regenerative Ca 2+ release a coincidence detector for metabotropic glutamate receptor (mGluR) or muscarinic acetylcho-line receptor (mAChR) activation (which mobilizes IP 3 ) and postsynaptic Ca 2+ signalling (from bAPs or dendritic Ca 2+ spikes) in pyramidal neurons 17,22,38 and Purkinje neurons 39 . The timing window for this synergistic response varies from 100 to 500 ms 17,38,39 . The duration of the window is closely related to the lifetime of IP 3 in the dendritic region where the wave is generated, which is determined by a combination of IP 3 degradation, IP 3 diffusion and IP 3 unbinding from the receptor 38,40 .…”

“…The timing window for this synergistic response varies from 100 to 500 ms 17,38,39 . The duration of the window is closely related to the lifetime of IP 3 in the dendritic region where the wave is generated, which is determined by a combination of IP 3 degradation, IP 3 diffusion and IP 3 unbinding from the receptor 38,40 . If diffusion is the dominant factor, as seems to be the case in pyramidal neuron dendrites, then the timing window will be smaller if the spatial extent of Ca 2+ release is more restricted because diffusional dissipation is more rapid in this case.…”

Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

“…The lifetime of an Ins(1,4,5)P 3 molecule is determined chiefly by its rate of metabolism, and possibly by the presence of Ins(1,4,5)P 3 buffering proteins. The functional lifetime of an Ins(1,4,5)P 3 molecule is also subject to passive diffusion [87]. As locally generated Ins(1,4,5)P 3 equilibrates in a cell, its concentration may fall below its affinity for binding ITPR, silencing the signal.…”

“…One recent study examined Ins(1,4,5)P 3 lifetime in CA1 pyramidal neurons using hippocampal slices and Ins(1,4,5)P 3 released by photolysis [87]. They concluded that the major determinant of the timing window for Ins(1,4,5)P 3 -regulated coincidence detection with action potentials was simply Ins(1,4,5)P 3 diffusion, rather than metabolism.…”