Endoplasmic reticulum: Regulator of structural potentiation of dendritic spines

Since the first electron micrograph of “lace-like structures” over 75 years ago, the endoplasmic reticulum (ER) is now viewed as a highly dynamic, constantly remodeling, continuous network of tubules and cisternae that plays an important role in a broad range of cellular activities from calcium regulation to protein synthesis and trafficking. In neurons, the ER extends from the soma through the axon to presynaptic terminals, and throughout the dendritic arbor into as many as half of all postsynaptic dendritic spines at any given time (Falahati et al., 2022). Dendritic spines are small protrusions decorating the branches of the dendritic arbor which receive most of the excitatory synaptic inputs in the central nervous system. Spines compartmentalize the postsynaptic mechanical and chemical responses tailored to the specific input that they receive. In addition to the wide range of shapes and sizes, spines also vary in their molecular and organellar composition, including ER. Recent findings reveal that neurons effectively exploit spine heterogeneity, particularly ER content to differentially tune spine function and structure during synaptic plasticity (Dittmer et al., 2024). Functional long-term potentiation (LTP) in response to strong high-frequency (HF) excitatory input relies heavily on postsynaptic Ca2+ signaling involving ionotropic glutamate receptors, mostly N-methyl-D-aspartate (NMDA) receptors and to a lesser extent Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors along with voltage-gated Ca2+ channels, predominantly L-type Ca2+ channels (LTCCs). Activity-driven Ca2+ signals activate multiple postsynaptic plasticity pathways, most notably Ca2+/calmodulin-dependent protein kinase II (CaMKII), to drive the insertion of AMPA receptors into the postsynaptic density to potentiate synaptic efficacy, a classic feature of LTP. In ER containing (ER+) spines, ER acts as a “Ca2+ store” that is mobilized by HF stimulation to enhance postsynaptic Ca2+ signals and synaptic potency (Konietzny et al., 2023; Dittmer et al., 2024). Mechanistically, strong HF stimulation at a single dendritic spine evokes glutamate binding to NMDA receptors which depolarize the plasma membrane (PM) and in turn gate LTCC Ca2+ entry. ER provides an added layer to Ca2+ signaling in spines, where LTCC-specific Ca2+ influx induces Ca2+ release from the ER via ryanodine receptors (RyR) leading to depletion of ER luminal Ca2+ that activates ER-Ca2+ sensor, stromal interaction molecule 1 (STIM1). Once activated STIM1 translocates to ER-PM junction where it opens Orai1 store-operated Ca2+ entry channels (Figure 1A; Dittmer et al., 2024). Recent three-dimensional reconstructions from electron microscopy images reveal ER closely juxtaposed to the PM in spines providing clear evidence of ER-PM in spines (Konietzny et al., 2023). Now universally accepted, ER-PM contact sites are abundant in neurons, serving as signaling hubs for lipid homeostasis and Ca2+ dynamics, in particular, repletion of ER Ca2+ stores via the action of the sarco-endoplasmic reticulum ATPase pump. Clearly, these ER Ca2+ store-related pathways are absent in ER lacking (ER–) spines.Figure 1: Differential potentiation of Ca 2+ signals and spine size imposed by endoplasmic reticulum (ER) content.(A) Mechanism for generating high-frequency (HF) glutamate (Glu)-evoked Ca2+ signals in ER– and ER+ spines involving L-type Ca2+ channel (LTCC) (●●), N-methyl-D-aspartate receptor (NMDAR) (●●), ryanodine receptors (RyR) (●●), Orai1 channels (●●) and stromal interaction molecule 1 (STIM1) (■). V indicates a change in membrane potential that activates LTCCs. (B) Graphical illustration of early phase (E)- structural long-term potentiation (sLTP) expression in ER– spines in response to a single HF stimulation train and stable integration of spine ER promoting the STIM1 – Orai1 channel interaction and late-phase (L)-sLTP in response to a well-spaced subsequent HF stimulation train. Low-frequency (LF) stimulation for induction of structural long-term depression (LTD). (C) Graphical illustration of the STIM1 – Orai1 channel interaction and L-sLTP expression in “responsive” ER+ spines in response to a single HF stimulation train, while no response in “refractory” ER+ spines to a well-spaced subsequent HF stimulation train or a single HF stimulation train. Created with the latest version of Adobe Creative Suite.HF stimulation that elicits postsynaptic Ca2+ signals also triggers spine enlargement known as structural LTP (sLTP). Structural LTP is defined by its time-specific phases. For instance, the transient early phase of sLTP (E-sLTP) is independent of de novo protein synthesis and shows a rapid response to strong HF postsynaptic stimulation that typically lasts for ~an hour, consistent with short-term memory. Alternatively, sLTP can persist for several hours or more, known as the late phase of sLTP (L-sLTP). L-sLTP relies on de novo protein synthesis and long-lasting rearrangement of spine structure, therefore thought to be associated with long-term memory. Thus, an important question in neuroscience remains. “What underlying factors determine how a spine expresses sLTP?” Until recent developments, the prevailing opinion in the field was based on the seminal study from Matsuzaki et al. (2004) that smaller spines undergo L-sLTP, while larger spines can only achieve E-sLTP, unable to develop L-sLTP. However, a recently published work from Dittmer et al. (2024) indicates that anatomical features of the spine, specifically ER content direct sLTP expression. This report confirms that approximately half of all examined spines lack ER and only express E-sLTP in response to strong HF stimulation. The estimated pre-stimulation volumes of these ER– spines broadly range from 0.01 to 0.49 µm3. Interestingly, during strong HF stimulation, several ER– spines receive brief, transient visits from the ER, but are unable to retain ER at the completion of the stimulation train shown in Figure 1B (Dittmer et al., 2024). Moreover, in Figure 1C, ER+ spines fit into two categories: (1) a “responsive” large population of ER+ spines consisting of approximately 40% of all examined spines with estimated pre-stimulation volumes ranging from 0.03 to 0.40 µm3 experience L-sLTP maintenance and (2) a “refractory” small population of ER+ spines comprising only approximately 10% of all examined spines show estimated pre-stimulation volumes ranging from 0.08 to 0.53 µm3 with approximately twice the ER content of “responsive” ER+ spines. These ER+ spines express attenuated E-sLTP and are refractory to L-sLTP. Considering these findings, the nature of sLTP in an individual spine is more complicated than the previously proposed two-state system based on initial spine size, which may be remedied by considering the ER content as a gauge for how a spine will express sLTP in response to strong synaptic stimulation. Architectural diversity in a population of spines reflects how precisely cytoskeletal machinery is tuned to synaptic activity. Genetic and pharmacological experiments reveal that activity-evoked rearrangement of long and short-branching actin filaments of the cytoskeletal network forms the basis for structural dynamics related to plastic changes in spine size and shape. On the rails of the spine’s actin network, ER moves into and within highly active spines aided by F-actin-associated motor proteins, specifically the family of myosin V (myoV) motors (Konietzny et al., 2023). Interestingly, with a single train of HF stimulation, ER is transiently carried into previously unoccupied ER– spines, but only stably integrated as spine ER with a well-timed subsequent train of strong HF postsynaptic stimulations, which also renders these spines amenable to persistent L-sLTP shown in Figure 1B (Dittmer et al., 2024). In contrast, ER+ spines enlarge accompanied by ER remodeling in response to a single train of HF stimulation, which is refractory to additional increases in size, ER content, or L-sLTP in response to subsequent trains of postsynaptic stimulation (Figure 1C). The insensitivity of “refractory” ER+ spines confirms that the ER-cytoskeleton association also promotes long-term spine and spine ER stability (Dittmer et al., 2024). In fact, “refractory” ER+ spines are typically rich in synaptopodin, an actin-associated protein known as a marker for the highly organized ER-derived organelle called the spine apparatus (Falahati et al., 2022; Konietzny et al., 2023). The spine apparatus is formed and stabilized through association with the myoVa protein, a member of the myosin V motor family (Konietzny et al., 2023). In addition to providing protection against runaway potentiation, refractory ER+ spines display a high propensity for long-term depression signified by spine shrinkage and synaptic weakening when subjected to low-frequency stimulation, perhaps a mechanism for resetting spine size and synaptic strength for future potentiation (Konietzny et al., 2023). Akin to Ca2+ amplification in ER+ spines, genetic and pharmacological manipulations confirm that both long-lasting expression of L-sLTP and the accompanied remodeling of spine ER require LTCC Ca2+ induction of RyR-dependent Ca2+ release activation of STIM1-dependent Orai1 channel Ca2+ entry (Dittmer et al., 2024). This finding raises the question of whether the additional rise in ER+ spine Ca2+ via RyR-dependent Ca2+ release from the ER and store-operated Orai1 channel Ca2+ entry is required for the development of L-sLTP in “responsive” ER+ spines. Unexpectedly, the resulting STIM1-Orai1 interaction at ER-PM junctions, but not the elevation in Ca2+ signals, is necessary for sustained ER content enrichment and L-sLTP expression in “responsive” ER+ spines (Dittmer et al., 2024). Yet, since STIM1 deactivates and dissociates from Orai1 channels with ER Ca2+ repletion several minutes after HF stimulation, it is likely that ancillary proteins, including STIM2 and junctophilins (JPHs), are recruited to the STIM1-Orai1 interaction at ER-PM junctions for stability and maintenance of activity-based L-sLTP expression and spine ER enrichment. In most cell types, STIM1 expression is much higher than STIM2, except in the nervous system. High expression levels infer specialized functions for STIM2 in the brain. STIM2 has a ~ twofold lower affinity for Ca2+ than STIM1 and thus requires a relatively small reduction in ER Ca2+ concentrations for STIM2 to aggregate and translocate to ER-PM junctions. Its proximity to ER-PM junctions due to partial activation at basal ER Ca2+ levels makes STIM2 an ideal homeostatic regulator of basal Ca2+ and well-positioned for regulating the delivery of AMPA receptors to the cell membrane (Bouron et al., 2015). Besides STIM2, JPHs are important junctional anchor proteins that contribute to the formation and stability of ER-PM junctions necessary for facilitating ER-PM signaling. Two family members, JPH3 and JPH4, are broadly expressed throughout the central nervous system, essential for coupling cell surface channels and receptors to ER signaling pathways. The connection between JPH4 and STIM proteins, specifically STIM1, perhaps also STIM2, is apparent by the necessity of ER-PM junction localized JPH4-junctate complex for Orai1-STIM1 clustering through the direct recruitment of STIM1. This connection is further supported by the evidence that STIM1-driven Orai1 channel Ca2+ entry is strongly impaired with the knockdown of JP4 expression (Hall et al., 2024). However, to truly implicate the activity-driven STIM1-Orai1 interactions as a nucleation site for the assembly of these and/or other ancillary proteins, follow-up studies are necessary. Inexplicably, how might these activity-driven STIM1-Orai1 junctions synchronize spine ER remodeling and spine enlargement? Recent studies report that STIM1 facilitates ER remodeling through an association with the end-binding protein 1 and the plus-end of elongating microtubules along with activity-induced release of brain-derived neurotrophic factor triggering microtubules coupling to actin polymerization for spine enlargement (Grigoriev et al., 2008; Dent et al., 2017). Together, these findings support STIM1-Orai1 junctions as a dual regulator of both potentiation of spine size and ER remodeling. Similarly, STIM2 associates with the closely related EB3 protein to stabilize spine structure (Pchitskaya et al., 2017). In fact, this novel role for the physical interaction between STIM1 proteins and Orai1 channels in the regulation of postsynaptic structural plasticity and spine ER remodeling represents a pathway dependent upon physical interactions within channel complex at ER-PM junctions, and not ion influx, in the vein of excitation-contraction coupling in skeletal muscle. In excitation-contraction coupling, the physical interaction between the gating of PM-embedded skeletal muscle LTCC channels, CaV1.1, and RyR 1 in the sarcoplasmic reticulum, but not CaV1.1 channel Ca2+ influx, links excitation by the nervous system to mechanical contraction of muscle fibers. Thus, the discovery of this novel role for STIM1-Orai1-based contacts adds to an exciting line of research into how signaling complexes at membrane junctions form and participate in a myriad of known neuronal functions and some are yet to be identified. This work was supported by AHA Career Development Award 938683 (to PJD) and NIH grant R01MH123700 (to MLD). Presentation at a meeting: FASEB The Ion Channel Regulation Conference, Nova Scotia, Canada; August 14–19, 2022. Open peer reviewer:Martin Heine, Johannes Gutenberg University, Germany. Additional file:Open peer review report 1.P-Reviewer: Heine M; C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

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