Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines

Abstract

Key points Calcium (Ca2+) 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) Ca2+ stores. The ER has a heterogeneous distribution in CA1 dendritic spines, and may introduce localized functional differences in Ca2+ signalling between synapses, as suggested by experiments on metabotropic receptor‐dependent long‐term depression. A physiologically detailed computational model of Ca2+ dynamics at a CA3–CA1 excitatory synapse characterizes the contribution of spine ER via metabotropic signalling during plasticity induction protocols. ER Ca2+ release via IP3 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 (Ca2+) 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 IP3‐sensitive Ca2+ stores affect spine Ca2+ 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 Ca2+‐based plasticity, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our study provides a biophysically accurate description of postsynaptic Ca2+ regulation, and suggests that ER in the spine may promote the re‐use of hippocampal synapses with saturated strengths.

Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses

“…Synapses with a low initial probability of release are capable of facilitation and function as high-pass filters, and the reverse is true for synapses with a high initial probability of release 64 – 66 . Other reported functions of short-term plasticity include insulating postsynaptic terminal from direct stream of presynaptic activity, spike sequence decorrelation, working memory, and, optimizing energy consumption and information transmission 67 – 71 .…”

Morphological principles of neuronal mitochondria

“…Recently, a series of studies on synaptic geometry and structural plasticity have been conducted by us and others [4,3,26,8]. Parallel studies have focused on the role of the ER and mitochondria in regulating the spine calcium and how internal organelles can alter the calcium and ATP dynamics [14,25,44].…”

Deciphering the postsynaptic calcium-mediated energy homeostasis through mitochondria-endoplasmic reticulum contact sites using systems modeling

“…We recognize that a stochastic approach would likely give rise to insights in limit cases of few molecules or in noisy environments [37,38]. Finally, we note that a more complete Ca 2+ influx model would account for voltage-gated calcium channel dynamics as well [22,24,60,61]. This is a focus of technical development and ongoing effort in our group.…”

“…Computational modeling has played a pivotal role in providing insight into calcium dynamics in neurons [22][23][24]. Bertram et al [25], Han et al [26], Wacquier et al [27] and others have created models addressing the role of calcium in mitochondria.…”