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Review
. 2019 Nov:95:120-129.
doi: 10.1016/j.semcdb.2019.01.006. Epub 2019 Jan 12.

From membrane receptors to protein synthesis and actin cytoskeleton: Mechanisms underlying long lasting forms of synaptic plasticity

Joanna Jędrzejewska-Szmek  1 , Kim T Blackwell  2
Affiliations
Review

From membrane receptors to protein synthesis and actin cytoskeleton: Mechanisms underlying long lasting forms of synaptic plasticity

Joanna Jędrzejewska-Szmek et al. Semin Cell Dev Biol. 2019 Nov.

Abstract

Synaptic plasticity, the activity dependent change in synaptic strength, forms the molecular foundation of learning and memory. Synaptic plasticity includes structural changes, with spines changing their size to accomodate insertion and removal of postynaptic receptors, which are correlated with functional changes. Of particular relevance for memory storage are the long lasting forms of synaptic plasticity which are protein synthesis dependent. Due to the importance of spine structural plasticity and protein synthesis, this review focuses on the signaling pathways that connect synaptic stimulation with regulation of protein synthesis and remodeling of the actin cytoskeleton. We also review computational models that implement novel aspects of molecular signaling in synaptic plasticity, such as the role of neuromodulators and spatial microdomains, as well as highlight the need for computational models that connect activation of memory kinases with spine actin dynamics.

Keywords: Actin; Computational model; LTD; LTP; Synaptic tagging; Translation.

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Figures

Figure 1.
Figure 1.
Three processes involved in L-LTP. Induction of L-LTP refers to molecules transiently activated during the stimulation protocol and is blocked by inhibitors applied during stimulation, yielding E-LTP. Maintenance of L-LTP refers to molecules persistently activated after the stimulation protocol, which can be blocked even after L-LTP has been observed. Expression refers to the molecules required for measurement of the change in synaptic strength, and re-appears after inhibitors are removed.
Figure 2.
Figure 2.
Calcium activates several key molecules that are critical for synaptic plasticity. Calcium directly binds to calmodulin, calpain and PKC. Calcium bound calmodulin activates adenylyl cyclase (AC1/8), CaMKII, RasGRF, and calcineurin. Adenylyl cyclase, synergistically activated by Gs coupled receptors, produces cAMP, which activates PKA and Epac. Both RasGRF and Epac activate monomeric GTP binding proteins. CaMKII, PKA and PKC all phosphorylate AMPA receptors, whereas PP1 and calcineurin dephosphorylate AMPA receptors. PKAc: catalytic subunit of PKA.
Figure 3.
Figure 3.
Numerous signaling pathways contribute to ERK activation. cAMP contributes to ERK through activation of Epac and PKA. Calcium activated molecules such as RasGRF and PKC can activate ERK through activation of Ras family proteins or phosphorylation of Raf isoforms. BDNF binds to TrkB receptors and then activates Ras family proteins through several scaffolding proteins. In all cases, a series of three events activates ERK: Ras family protein binding to the kinase Raf, Raf phosphorylating MEK at two sites, and then MEK phosphorylating ERK at two sites. Dashed lines indicate that additional molecules may be intermediaries.
Figure 4.
Figure 4.
Several memory kinases interact with actin binding proteins to remodel the spine actin cytoskeleton. CaMKIIβ both cross-links f-actin and buffers g-actin monomers. Binding of CaMKII to calmodulin decreases g-actin binding making g-actin monomers available and facilitating cofilin cleavage of f-actin. Both CaMKII and PKA enhance Kalirin7 activity through phosphorylation, allowing it to activate monomeric GTP binding proteins Rac1 and cdc42. Their targets include WAVE and WASP members of the ARP2/3 complex (needed for new actin branches) and PAK. Both PAK and PKA phosphorylate (to inactivate) LIMK, which phosphorylates (to inactivate) cofilin. Calcineurin dephosphorylates (to activate) SSH which then dephosphorylates (to activate) cofilin. PKAc: catalytic subunit of PKA.
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