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Integration of biochemical signalling in spines

Key Points

  • The complex integration of biochemical signalling pathways in and near synaptic spines allows excitatory synapses to store information by modulating their strength and individual neurons to maintain homeostatic balance.

  • Spine signalling machinery is tuned so that small changes in the influx of the second messenger Ca2+ can produce widely divergent functional outcomes. For example, during spike-timing-dependent synaptic plasticity, relatively large and rapid influxes of Ca2+ into the spine produce long-term potentiation, whereas more prolonged and lower influxes of Ca2+ produce long-term depression.

  • Two emerging concepts that concern the organization of signalling cascades contribute to our understanding of the integration of signalling in spines. First, signalling pathways, once believed to be mostly linear, interact extensively with each other to form networks; and, second, the intracellular locations of signalling proteins are carefully controlled by subcellular targeting and interactions with scaffold proteins.

  • Several physiological processes that are crucial for synaptic plasticity and/or neuronal homeostasis are coordinately controlled by spine signalling pathways. These include the number and efficacy of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors, assembly of the actin cytoskeleton, local protein synthesis, new gene expression in the nucleus and the initiation of apoptosis.

  • The signalling pathways that participate in coordinated control include: Ca2+ and cyclic AMP (cAMP) second messenger pathways, which are regulated by NMDA (N-methyl-D-aspartate)-type glutamate receptors and metabotropic receptors; Src family protein tyrosine kinases, which are regulated by metabotropic receptors and ephrin B receptors (EphBs); and the small GTPases Ras, Rap, Rac and Cdc42 (from cell division cycle 42), which are regulated by NMDA receptors, tyrosine receptor kinase B (TrkB), EphBs and by the Ca2+ and cAMP second messenger pathways.

  • The poster accompanying this review summarizes studies on the signalling network that regulates postsynaptic function in and near the spine, and presents an initial attempt to understand how the network is organized.

  • The field is at a juncture where rigorous quantitative models are needed that incorporate the spatial localization of signalling proteins and measured kinetic parameters of signalling events that can lead to changes in spine functions. Such models can act as an aid in understanding the consequences of our assumptions about the kinetics of the reactions in a network and the organization of proteins that participate in them, and can be used to design quantitative experimental tests of those assumptions.

  • The map of the signalling network presented here is not meant to be exhaustive or definitive; rather, it is meant as a starting point for quantitative efforts to refine our understanding of the integration of signalling pathways in the spine.

Abstract

Short-term and long-term changes in the strength of synapses in neural networks underlie working memory and long-term memory storage in the brain. These changes are regulated by many biochemical signalling pathways in the postsynaptic spines of excitatory synapses. Recent findings about the roles and regulation of the small GTPases Ras, Rap and Rac in spines provide new insights into the coordination and cooperation of different pathways to effect synaptic plasticity. Here, we present an initial working representation of the interactions of five signalling cascades that are usually studied individually. We discuss their integrated function in the regulation of postsynaptic plasticity.

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Figure 1: Signalling from the NMDA receptor to Ras, Rap, Rac and Cdc42.
Figure 2: New scaffolding interactions in the postsynaptic density.

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Acknowledgements

This work was supported by grants from the National Institutes of Health to M.B.K., fellowships from the National Institutes of Health to H.J.C. and to the Division of Biology for support of H.C.B., and a fellowship from the John Douglas French Alzheimer's Foundation to L.R.W. We thank E. Marcora of the Kennedy lab for valuable comments on the manuscript.

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Correspondence to Mary B. Kennedy.

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DATABASES

Entrez Gene

CalDAG-GEF1

CalDAG-GEF2

cAMP-GEF

RasGRF1

SPAR

SynGAP

TIAM1

FURTHER INFORMATION

Mcell

DReAMM 

POSTER

Integrated biochemical signalling in postsynaptic spines

Glossary

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory-postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured as an increase in the amplitude of excitatory-postsynaptic potentials or in the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

TAT PEPTIDES

These are protein domains of interest, fused to the carboxyl terminus of the 11-residue protein transduction domain (PTD) of the human immunodeficiency virus 1 (HIV-1) transcriptional activator Tat protein. The Tat PTD allows the TAT peptide to be taken up into cells by macropinocytosis and then to move across the vesicle membrane into the cytosol.

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Kennedy, M., Beale, H., Carlisle, H. et al. Integration of biochemical signalling in spines. Nat Rev Neurosci 6, 423–434 (2005). https://doi.org/10.1038/nrn1685

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