Trends in Neurosciences
ReviewArc in synaptic plasticity: from gene to behavior
Introduction
The molecular basis of learning and memory involves modifying neuronal synapses in response to electrical activity, a process termed synaptic plasticity. Memory formation has been divided into two temporal phases. Short-term memory formation involves changes to synaptic efficacy by modifying existing proteins. Long-term memory formation requires new gene transcription and protein production to stabilize recent changes. These long-term changes to synaptic strength take several forms. In long-term potentiation (LTP), specific synapses are strengthened. In long-term depression (LTD), specific synapses are weakened. In homeostatic plasticity, neuron-wide shifts in responsiveness maintain the maximal sensitivity of the neuron to future activity-dependent synaptic plasticity.
Arc is specifically required for long-term memory formation and affects all of these forms of synaptic plasticity. Arc, also known as Arg3.1, is found only in vertebrates but is highly conserved in this group 1, 2. Glutamatergic neurons in the brain express Arc in response to an increase in synaptic activity in a range of behavioral and learning paradigms 3, 4, 5, 6. Localization and stability of the transcript and protein are also highly regulated. Arc protein is not found in presynaptic terminals or axons but is highly expressed in dendrites 7, 8, the postsynaptic density 7, 9, 10 and the nucleus 11, 12. Arc regulates endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) 13, 14, Notch signaling [15], and spine size and type [16].
These distinct actions all modify synaptic strength. Removal of Arc in knockout (KO) animals results in an unusual phenotype: short-term learning is normal but lasting memories cannot be formed [17]. Arc, therefore, provides a means to understand the cellular processes of memory consolidation. However, Arc has multiple functions and responds differently to different stimuli and signaling pathways. Although much is known about how Arc is regulated and affects synaptic strength, defining a coherent mechanism for its role in synaptic plasticity and memory consolidation has proven difficult. Recent reviews eloquently described known mechanisms of Arc regulation and function in plasticity 18, 19, 20, 21, 22, 23, 24. Here, we will summarize and update these findings. In addition, we will discuss how Arc's functions might contribute to its effects on synaptic plasticity and its role in disease.
Section snippets
Regulation of Arc transcription
In 1995, two labs independently identified Arc as a gene induced by seizures in the hippocampus 1, 2. Arc expression is also induced by the increased neuronal activity that occurs in response to learning 4, 25, brain-derived neurotrophic factor (BDNF) 26, 27, LTP 7, 28, LTD 29, 30 and other stimuli. Arc transcripts appear within 5 min of stimulation [4], which makes Arc a ‘rapid’ immediate early gene. Such genes have transcriptional machinery poised just downstream of the start site, allowing
Regulation of Arc mRNA
Once Arc mRNA is transcribed, it undergoes further regulation before being translated. At 30 min after stimulation, Arc mRNA is exported from the nucleus to the cytoplasm and, by 1 h, can travel to the most distal tips of dendrites 32, 40. The speed of Arc mRNA movement (up to 65 μm/min [41]) and its localization to the kinesin motor complex [42] imply active transport. Other components of the Arc messenger ribonucleoprotein complex (mRNP) include fragile X mental retardation protein (FMRP) and
Regulation of Arc protein production and clearance
Similar to Arc transcription, Arc translation also seems to be highly controlled by activity levels and specific signaling cascades. Stimulation of NMDARs and Gs-coupled receptors in cultured neurons increases Arc translation in a manner dependent on PKA [49]. LTP-induced Arc translation in vivo requires ERK signaling through MAP kinase-interacting kinase (MNK), which phosphorylates eIF4E [50]. mGluR-LTD can result in immediate translation of pre-existing mRNA in a manner dependent on
Regulation of Arc by behavior
Behavioral tasks that induce Arc expression range from a simple sound exposure [53] to complex tasks such as reversal learning in a T-maze [5]. The tight link between synaptic activity and Arc transcription led to widespread use of Arc RNA as a means of determining what neurons are activated in response to various learning paradigms. Arc RNA appears in the nucleus within a few minutes of neuronal activation and is predominately localized to the cytoplasm by 30 min. In situ hybridization,
Arc function in structural plasticity
Synaptic plasticity takes several forms, including modification of synapse structure and strength. Synaptic structure is modified in neurons in response to changes in neuronal activity, and stabilization of spines is associated with long-term memory formation [58]. The original observations that Arc cofractionates with actin [1] and that changes in actin cytoskeleton are required for changes in spine structure [59] led to an investigation of the role Arc has in structural plasticity. In
Arc function in Hebbian plasticity
In addition to modifying synaptic structure, Arc also regulates synaptic strength. Knockdown and KO studies show that Arc is required for the late phase of LTP. Arc KO mice show a steady decline of potentiation after an initial enhanced response to high frequency stimulation (HFS) [17]. The initial enhancement is not seen with acute manipulations of Arc levels, therefore it is most probably a result of some developmental compensation in response to a lifelong deficit in Arc expression. However,
Arc function in homeostatic plasticity
LTP and LTD are self-reinforcing mechanisms and might push synaptic strength to one extreme or another if left unchecked. This can reduce the capacity of the system to respond to additional changes in activity and might also make the network unstable, leading to conditions such as epilepsy. To prevent such extremes, a neuron responds to long-term increases or decreases in activity by scaling its response to activity down or up, respectively, to maintain the same average firing rate. This
Arc function in behavior
Arc's importance in the late phases of LTP and LTD indicates that it is likely to have an important functional role in late phases of learning and memory. Interestingly, Arc KO mice learn new behavioral tasks in a similar manner to control mice, but cannot consolidate new memories [17]. For example, at 10 min after exposure to an object, KO and wild type mice have achieved the same preferences for a novel object over the original one, indicating that KO mice can learn and remember within this
Arc in aging and disease
Although no diseases are known to be caused by mutations directly related to Arc expression, the loss of Arc in KO mice leads to hyperexcitability and increased susceptibility to seizures [16]. Interestingly, increased levels of Alzheimer's-related human amyloid precursor protein (hAPP)-derived amyloid β in transgenic mice expressing hAPP [77] and in cultured cortical neurons [78] impaired Arc expression and also led to hyperexcitable networks and seizures [79]. Indeed, the extent to which Arc
Conclusions and future directions
Arc plays a vital role in the molecular mechanisms underlying memory consolidation. Its expression is tightly linked to neuronal activity, and this finding has led to its use as a tool to study both functional and dysfunctional neurons. Given its enrichment at synapses and in the nucleus, and its pleotropic roles in Hebbian and homeostatic plasticity, Arc probably mediates its effects on behavior through multiple cellular functions, including regulation of AMPAR endocytosis, spine morphology
Acknowledgments
We thank G. Howard for editorial input. E.K. was supported by a Ruth L. Kirschstein Fellowship (5 F31 MH087009). Primary support was provided by the National Institute of Neurological Disease and Stroke (2 R01 NS39074), the National Institute on Aging (2 P01 AG022074), the J. David Gladstone Institutes (S.F.), the Hellman Family Foundation Program in Alzheimer's Disease Research, and the Keck Program for Striatal Physiology and Pathophysiology (S.F.). We apologize to our colleagues whose
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