Order-Dependent Coincidence Detection in Cerebellar Purkinje Neurons at the Inositol Trisphosphate Receptor

Abstract

Associative long-term depression (LTD) at cerebellar parallel fiber-Purkinje cell synapses is sensitive to the temporal order in which the parallel fiber is coactivated with the climbing fiber input, but how order sensitivity is achieved is unknown. Here we show that the cerebellar inositol-1,4,5-trisphosphate (IP 3 ) receptor, whose activation is required for LTD induction, is sensitive in situ to the order of presentation of its coagonists, IP 3 and cytoplasmic calcium. By focally photolyzing a novel caged IP 3 compound in dendritic spines, we find that pairing IP 3 with climbing fiber-mediated calcium entry leads to a large calcium release transient if the climbing fiber is activated up to 100 ms before or up to 500 ms after IP 3 uncaging. This asymmetric timing window for coactivation follows the kinetics of calcium removal and IP 3 unbinding from the receptor and is not limited by IP 3 metabolism. IP 3 receptor binding thus acts as an eligibility trace that can drive temporal order-dependent calcium release and LTD induction in Purkinje cells and event order-dependent sensory plasticity in the whole animal.

The Calcium Kinetics and Inositol Trisphosphate Receptor Properties Shape the Asymmetric Timing Window of Coincidence Detection

“…To rule out the possibility that IP 3 -induced calcium release activates potassium conductance and enhances climbing fiber-evoked calcium entry to the hyperpolarized dendrite, they visualized calcium signals along the dendrite. As expected, the spatial distribution of supralinear calcium responses was much more restricted than that of electrical potentials [Sarkisov and Wang (2008), their Fig. 4 (http://www.jneurosci.org/cgi/ content/full/28/1/133/F4)], indicating that potassium conductances are unlikely to be responsible for the supralinearity.…”

“…To answer this question, Sarkisov and Wang (2008) explored the coincidence detector properties of the IP 3 receptor in Purkinje cells by photolyzing doublecaged IP 3 , which is less antagonistic to the IP 3 receptor and offers a higher spatial resolution of focal uncaging than its singlecaged counterpart (Sarkisov et al, 2007). Coincident presentation of IP 3 and climbing fiber activation triggered calcium signals in Purkinje cells that were substantially larger than the linear sum of the signals from climbing fiber and IP 3 alone [Sarkisov and Wang (2008), their Fig.…”

“…1 (http://www.jneurosci.org/cgi/content/ full/28/1/133/F1)]. Climbing fiber activation up to 100 ms before or up to 500 ms after IP 3 uncaging resulted in synergistic calcium release [Sarkisov and Wang (2008) . Calcium responses were sensitive to the order of IP 3 uncaging and climbing fiber activation, and the maximal signals were observed when the climbing fiber was activated 100 -200 ms after IP 3 uncaging; they reached 0.6 -1.8 M in spines and 0.3-0.7 M in spiny dendrites [Sarkisov and Wang (2008)…”

“…This optimal delay of climbing fiber inputs is consistent with their putative role in associative learning as teaching signals. Coincidence-dependent supralinearity emerged in a shorter time than enzymatic reactions take [Sarkisov and Wang (2008), their Fig. 3 (http://www.…”

“…Next, by using a calcium-store depletor and an IP 3 receptor blocker, the authors demonstrated that supralinear cal-cium signals resulted from IP 3 receptormediated calcium-induced calcium release from internal stores [Sarkisov and Wang (2008) (Wang et al, 2000). To rule out the possibility that IP 3 -induced calcium release activates potassium conductance and enhances climbing fiber-evoked calcium entry to the hyperpolarized dendrite, they visualized calcium signals along the dendrite.…”