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Nari Shin
4 min read

Arc Protein: What Is It and How Does It Affect Cognitive Function?

Arc protein, or Activity Regulated Cytoskeleton Associated Protein, is a neuron-specific protein that develops memory formation through regulating synaptic plasticity in the mammalian brains of humans and animals. It is mainly expressed in the cortical and hippocampal glutamatergic neurons. Synaptic plasticity is the ability of a synapse’s strength to change depending on the frequency of use, which mainly fosters emotions, cognitive flexibility, and memory formation. These Arc proteins mainly regulate synaptic plasticity and function and this ability is attributed to their structure. 


Arc-protein is a member of the Immediate Early Gene (IEG) family, a network of proteins expressed from external physiological stimuli that function as indicators of neural activity. Although they do not encode transcription factors, their main function is to regulate transcription and act like transcription factors that affect the expression of delayed response genes involved in neural plasticity, which takes place at postsynaptic sites and undergoes biochemical modifications. The arc mRNA is transported to active dendritic spines to be translated and it further regulates AMPA receptors through endocytic machinery. It is activated in synaptic sites, in which the translated proteins play a crucial role in neural processes involving memory and learning. 


A unique aspect of arc-proteins is that it is the first neuronal protein to embody retrovirus structure. It was discovered that arc contains group-specific antigen amino acid sequences commonly found in retroviruses. These structures with spikes and putative internal RNA binding domains are formed by Arc homologs (Drosophila dArc1 and dArc2). The dArc1 plays a specific role in controlling fat metabolism and regulating synaptic plasticity at the neuromuscular junction. Due to its structural similarity, arc protein is therefore related to retrotransposons, genetic components that undergo reverse transcription (RNA to DNA) that function as gene regulation and base of mammalian genomes. Like retroviruses, arc Gag amino acids form capsids that package RNA and experience secondary envelopment to eventually be released into an extracellular vesicle pathway. The drosophila arc1 protein capsid structure binds its respective mRNA in the neurons and is released into the muscles through extracellular vesicles. The transfer of dArc1 between synaptic partners similar to that of a retrovirus has a major influence on the synaptic plasticity of mammals. 


Transcription of arc occurs by activating N-methyl-D-aspartate (NMDA)-type glutamate receptors and extracellular signal-regulated kinase (ERK) following Long term potentiation (LTP) and long-term depression (LTD) induction. The NMDA glutamate receptor is the primary excitatory neurotransmitter that affects synaptic plasticity. Calcium cells enter the cell through these NMDA receptors and also voltage-gated calcium channels (VGCCs), which activate calcium-dependent signaling cascades that activate transcription factors and induce target gene transcription. The ERK is effectors of the protein kinase signaling cascade activated by mitogens that regulate transcription and cell processes. Therefore, through the activation of protein kinase and ERK, it leads to increased levels of intracellular calcium and cAMP levels that induce arc in pheochromocytoma 12 cells and hippocampal neurons. It is induced pharmacologically in the hippocampal neurons by BDNF, DHPG, adenylate cyclase, or muscarinic acetylcholine receptors. BDNF induces synaptic activity, which is needed for BDNF-induced Arc expression. The NMDA receptors must also cooperate with AMPA-type glutamate receptors to regulate changes in synaptic efficacy and locate Arc mRNA. The AMPA receptors are negative regulators of arc dowregulate its expression through coupling AMPA receptor function to a pertussis toxin-sensitive G protein, which leave the stability and translation of arc mRNA unaffected. 


The structure of the arc affects the formation of long-term memory when the capsids alter the strength of the synapses on nearby neurons. Moreover, the lack of arc genes or a structural change in those proteins in animals prevents long-term memory formation, but allows short-term memories. When arc induction was prevented by shorthairpin RNA from pharmacological network activation, it also modified 1900 genes and their expression profile including synaptic function, neuronal plasticity, intrinsic excitability, and signaling pathways. Reduced arc expression in the hippocampus prevents synaptic plasticity and hippocampus-dependent learning and memory consolidation. Therefore, the pathways may involve the progression of neurodegenerative disorders such as Alzheimer's disease, a type of dementia that destroys memory and cognitive skills, and Fragile X syndrome, a genetic condition that impairs cognitive development. The lack of regulation of arc can also affect memory formation and regular brain functions, which can contribute to the pathogenesis of neurodevelopmental disorders, such as schizophrenia, a severe mental health condition. The development of schizophrenia, autism, and other conditions correlate with mutations in the arc gene. Arc accumulating in dendrites at sites of recent synaptic activity can help investigate the formation of memory, which can allow researchers to determine to prevent progression of these conditions. For instance, it has been discovered that the development of neurodegenative disorders can be possibly mediated with the transfer of prion-like proteins from cell to cell through exosomes or strengthening the synapses that connect neurons. However, the role of the arc-protein still needs to be researched continuously. Researching the arc-protein and its correlation to synaptic plasticity and cognitive function will allow scientists to investigate treatments for neurodegenerative and neurodevelopmental diseases that widely affect people all over the world.


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