Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines

KEY POINTS: Calcium (Ca(2+)) entry mediated by NMDA receptors is considered central to the induction of activity‐dependent synaptic plasticity in hippocampal area CA1; this description does not, however, take into account the potential contribution of endoplasmic reticulum (ER) Ca(2+) stores. The ER has a heterogeneous distribution in CA1 dendritic spines, and may introduce localized functional differences in Ca(2+) signalling between synapses, as suggested by experiments on metabotropic receptor‐dependent long‐term depression. A physiologically detailed computational model of Ca(2+) dynamics at a CA3–CA1 excitatory synapse characterizes the contribution of spine ER via metabotropic signalling during plasticity induction protocols. ER Ca(2+) release via IP(3) receptors modulates NMDA receptor‐dependent plasticity in a graded manner, to selectively promote synaptic depression with relatively diminished effect on LTP induction; this may temper further strengthening at the stronger synapses which are preferentially associated with ER‐containing spines. Acquisition of spine ER may thus represent a local, biophysically plausible ‘metaplastic switch’ at potentiated CA1 synapses, contributing to the plasticity–stability balance in neural circuits. ABSTRACT: Long‐term plasticity mediated by NMDA receptors supports input‐specific, Hebbian forms of learning at excitatory CA3–CA1 connections in the hippocampus. There exists an additional layer of stabilizing mechanisms that act globally as well as locally over multiple time scales to ensure that plasticity occurs in a constrained manner. Here, we investigated the role of calcium (Ca(2+)) stores associated with the endoplasmic reticulum (ER) in the local regulation of plasticity at individual CA1 synapses. Our study was spurred by (1) the curious observation that ER is sparsely distributed in dendritic spines, but over‐represented in larger spines that are likely to have undergone activity‐dependent strengthening, and (2) evidence suggesting that ER motility at synapses can be rapid, and accompany activity‐regulated spine remodelling. We constructed a physiologically realistic computational model of an ER‐bearing CA1 spine, and examined how IP(3)‐sensitive Ca(2+) stores affect spine Ca(2+) dynamics during activity patterns mimicking the induction of long‐term potentiation and long‐term depression (LTD). Our results suggest that the presence of ER modulates NMDA receptor‐dependent plasticity in a graded manner that selectively enhances LTD induction. We propose that ER may locally tune Ca(2+)‐based plasticity, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our study provides a biophysically accurate description of postsynaptic Ca(2+) regulation, and suggests that ER in the spine may promote the re‐use of hippocampal synapses with saturated strengths.