Local protein synthesis, actin dynamics, and LTP consolidation
Introduction
The immense capacity and specificity of memory storage in the mammalian central nervous system is thought to depend on the plasticity of neuronal communication at synapses. Dysfunction of synaptic plasticity is implicated in a range of disorders from Alzheimer’s disease to mental retardation and development of chronic pain states. Understanding how neural activity patterns are translated into lasting changes in synaptic connectivity that shape neural network functions and behavior is therefore a major goal. Glutamatergic synapses are capable of expressing diverse forms of activity-dependent potentiation and depression. Persistent forms of synaptic change, as seen in late phase long-term potentiation (LTP) and long-term depression (LTD), typically require rapid new gene expression and protein synthesis.
By modulating dendritic protein synthesis and degradation, synaptic inputs may directly remodel the protein composition, and thereby the functional state, of individual dendritic spines or spine clusters. Despite abundant evidence implicating dendritic protein synthesis in long-term synaptic plasticity, causal roles for specific activity-induced genes and dendritically synthesized proteins have been hard to define. In addition to protein synthesis, stable forms of LTP and LTD typically require modulation of actin dynamics in dendritic spines. This article summarizes and attempts to integrate recent advances on the role of Arc and other dendritic mRNAs as regulators of LTP consolidation and actin polymerization, the role of BDNF in activating Arc-dependent LTP consolidation as well as morphological expansion of spines, and the cell biological function of distinct actin pools within the spine. In this emerging picture, local protein synthesis controls long-term functional and structural plasticity of dendritic spines through regulation of actin cytoskeletal dynamics. Finally, these mechanisms are discussed in the context of actin regulation of protein exchange at the postsynaptic density (PSD) and the newly discovered phenomenon of protein sharing between neighboring synapses. Recent advances in dendritic RNA transport, localization, and translation have been discussed elsewhere and will not be covered in detail here [1, 2].
Section snippets
Arc and LTP consolidation
Arc is induced as an immediate early gene in vertebrate principal neurons. Learning paradigms are associated with rapid induction of Arc in many regions of the adult rodent forebrain. The mRNA encoded by Arc traffics to dendrites and specifically accumulates near stimulated synapses [3]. Following high-frequency stimulation (HFS) of the perforant path input to dentate granule cells of the dentate gyrus, Arc protein becomes locally enriched in dendritic spines. Arc is the only RNA known to
Local protein synthesis, F-actin, and structural plasticity
Formation of stable LTP at glutamatergic synapses involves enduring structural changes including expansion of the postsynaptic density and enlargement of dendritic spines [10, 11, 12, 13, 14, 15, 16••, 17]. In addition to NMDA receptor activation and calcium influx, these structural changes typically depend on actin polymerization. Numerous studies have shown that inhibition of actin polymerization attenuates LTP maintenance [10, 18, 19, 20]. LTD is likewise associated with actin filament
BDNF, spine actin, and control of LTP consolidation
Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) as a trigger of protein synthesis dependent LTP [32, 33]. HFS of excitatory input triggers release of BDNF leading to activation of postsynaptic TrkB receptors that can mobilize further BDNF secretion. Stimulus protocols generating late phase LTP are associated with a period of sustained BDNF release, and disruption of the BDNF-TrkB interaction blocks late phase LTP. Exogenous application of BDNF induces a
Actin function in spines
A major current issue is the organization and function of actin pools in dendritic spines [39]. Recent work sheds light on this topic in the context of long-term synaptic plasticity. Two distinct pools of actin filaments have been identified in mature spines: a dynamic pool with high turnover present in the tip of the spine and a more stable pool of actin filaments in the central core [40, 41].
Using two-photon activation of photoactivatable GFP (paGFP) fused to β-actin, researchers studied
Sharing, crosstalk, and capture in spine neighborhoods
Recent studies provide evidence for sharing of proteins between neighboring synapses [54••, 55•]. The scaffolding protein PSD-95 is a well-known determinant of PSD size and synaptic strength. In order to study PSD-95 dynamics at single spines in vivo, researchers used two-photon activation of PSD-95 tagged with either GPF or paGFP in layer 2/3 dendrites of mouse barrel cortex. This work revealed a dynamic pool of PSD-95 that is shared between neighboring spines [54••]. PSD-95 is retained in
Conclusions
LTP consolidation is a dynamic process in which the time and place of neuronal protein synthesis is dictated by post-transcriptional regulation. Our understanding of this process remains in its infancy, but recent research has given insight into specific molecular mechanisms that connect dendritic protein synthesis to regulation of actin cytoskeletal dynamics underlying long-term structural and functional plasticity. In the dentate gyrus, LTP consolidation requires sustained Arc translation
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The work is funded by European Union Marie Curie RTN grant GENE-MEMORY (504231) and the Norwegian Research Council.
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