Arc regulates spine morphology and maintains network stability in vivo

Gladstone Institute of Neurological Disease and the Keck Program in Striatal Physiology, San Francisco, CA 94158, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(42):18173-8. DOI: 10.1073/pnas.1006546107
Source: PubMed


Long-term memory relies on modulation of synaptic connections in response to experience. This plasticity involves trafficking of AMPA receptors (AMPAR) and alteration of spine morphology. Arc, a gene induced by synaptic activity, mediates the endocytosis of AMPA receptors and is required for both long-term and homeostatic plasticity. We found that Arc increases spine density and regulates spine morphology by increasing the proportion of thin spines. Furthermore, Arc specifically reduces surface GluR1 internalization at thin spines, and Arc mutants that fail to facilitate AMPAR endocytosis do not increase the proportion of thin spines, suggesting that Arc-mediated AMPAR endocytosis facilitates alterations in spine morphology. Thus, by linking spine morphology with AMPAR endocytosis, Arc balances synaptic downscaling with increased structural plasticity. Supporting this, loss of Arc in vivo leads to a significant decrease in the proportion of thin spines and an epileptic-like network hyperexcitability.

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Available from: Carol Wilkinson, Aug 10, 2015
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    • "Since the cytoplasmic Arc-positive cells at 30 min would represent neurons which had been activated about 20 min before [ie after the inhibited pMAPK peak (Guzowski et al., 1999)], we showed a strong correlation between the inhibited pMAPK peak in astrocytes of the S. rad and repression of neuronal Arc expression in the S. pyr. On the other hand, the still Arc-positive neurons at 15 min might represent neurons which might have either " escaped " the DMI inhibition, without being sufficient to show an overall synaptic potentiation, or might have even reinforced the inhibitory effect of DMI at synaptic locations, as far as an increased Arc activity in the post-synapse inversely correlates with internalization of AMPA receptors and synaptic stabilization (Peebles et al., 2010). Since only pMAPK in the S. rad showed a peak of activity after LTP induction, we hypothesized that the destabilization of Arc expression would depend on events occurring in the S. rad (non-cell autonomous effects). "
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    ABSTRACT: Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CA1 field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-positive cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Trycyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biological underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyse a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favoured an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the molecular and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clinical use of DMI.
    Full-text · Article · Jan 2016 · Neuropharmacology
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    • "Arc expression is required for LTM consolidation, but not for learning or short-term memory formation (STM; Plath et al., 2006). Arc knockout (KO) mice exhibit impaired consolidation of spatial and fear memories (Plath et al., 2006; Peebles et al., 2010; Yamada et al., 2011). Transient inhibition of Arc expression following infusion of Arc antisense oligodeoxynucleotides (ODNs) into the hippocampus, lateral amygdala, or anterior cingulate cortex inhibits memory consolidation (Guzowski et al., 2000; Ploski et al., 2008; Holloway and McIntyre, 2011; Nakayama et al., 2015). "
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    ABSTRACT: In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs) such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas.
    Full-text · Article · Jan 2016 · Frontiers in Molecular Neuroscience
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    • "Its expression is confined almost exclusively to excitatory neurons of the hippocampus and neocortex, with little or no expression in glia (Vazdarjanova et al., 2006). Arc is also involved in regulating dendritic spines via actin remodeling, as mice lacking Arc have reduced dendritic spine density (Peebles et al., 2010). Arc mRNA, which is induced by calcium influx through voltage-gated calcium channels and N-methyl-D-aspartate receptors (NMDARs), is trafficked to dendrites and synthesized at synaptic sites (Korb and Finkbeiner, 2011). "
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    ABSTRACT: Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. Arc protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. Arc transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR-/-), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR-/-) mice also have reduced Arc protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR-/- mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of Arc in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit Arc and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia.
    Full-text · Article · Jun 2014 · Neurochemistry International
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