Calcium Signaling in Dendritic Spines

Higley, Michael J.; Sabatini, Bernardo L.

doi:10.1101/cshperspect.a005686

Cited by 161 publications

(180 citation statements)

References 139 publications

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“…These transient fluxes (Ca 2þ transients) are mediated by Ca 2þ channels. [96][97][98] Activation of specific transmembrane channels increases the levels of Ca 2þ in the nucleus and the cytosol, including the cytosol's dendritic and axonal spaces. [99][100][101][102][103][104] Ca 2þ channels reside in the neuron's plasma membrane, particularly its synaptic regions, and also in intracellular membranes of the endoplasmic reticulum (ER), which is present in axons and dendrites as well.…”

Section: The Fragment Generation Hypothesismentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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Section: The Fragment Generation Hypothesismentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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“…It has been shown that less than five and, occasionally, only a single NMDA receptor opens under physiological conditions, causing a total Ca 2+ influx of about 6000 ions into a spine head reaching a concentration of ∼10 µm (Higley and Sabatini, 2012). However, the majority of the ions are rapidly eliminated by binding to Ca 2+ proteins, reaching ∼1 µM of free Ca 2+ concentration (Higley and Sabatini, 2012).…”

Section: Biological Plausibilitymentioning

confidence: 99%

“…However, the majority of the ions are rapidly eliminated by binding to Ca 2+ proteins, reaching ∼1 µM of free Ca 2+ concentration (Higley and Sabatini, 2012).…”

Section: Biological Plausibilitymentioning

confidence: 99%

“…Following membrane depolarisation, the co-agonists, Lglutamate and glycine must bind to their respective sites on the receptor to open the channel. On activation, the NMDA receptor allows the influx of extracellular calcium ions into the postsynaptic neuron and neurotransmission occurs (reviewed in Higley and Sabatini, 2012). Calcium flux through NMDA receptors is also thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory.…”

Section: How Does This Key Event Relationship Workmentioning

confidence: 99%

“…Calcium imaging techniques have been extensively utilised in the literature to investigate the potential interactions between NMDAevoked Ca 2+ influx and NMDA receptor activation. Approximately 15% of the current through NMDA receptors is mediated by Ca 2+ under physiological conditions (Higley and Sabatini, 2012).…”

Section: Biological Plausibilitymentioning

confidence: 99%

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Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

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OECD Series on Adverse Outcome Pathways

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Degeneracy in hippocampal physiology and plasticity

2019

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Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis that point to the expression of degeneracy in hippocampal physiology and plasticity. We assess the potential of degeneracy as a framework to achieve the conjoint goals of encoding and homeostasis without cross‐interferences. We postulate that biological complexity, involving interactions among the numerous parameters spanning different scales of analysis, could establish disparate routes towards accomplishing these conjoint goals. These disparate routes then provide several degrees of freedom to the encoding‐homeostasis system in accomplishing its tasks in an input‐ and state‐dependent manner. Finally, the expression of degeneracy spanning multiple scales offers an ideal reconciliation to several outstanding controversies, through the recognition that the seemingly contradictory disparate observations are merely alternate routes that the system might recruit towards accomplishment of its goals.

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Calcium Signaling in Dendritic Spines

Cited by 161 publications

References 139 publications

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

Degeneracy in hippocampal physiology and plasticity

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