Local protein synthesis in dendrites plays a significant role in synaptic plasticity. For example, the activity-regulated cytoskeleton-associated protein (ARC/ARG3.1), an immediate early gene, is required for many forms of synaptic plasticity and long-term memory formation. It has been reported that Arc transcription is rapidly induced after novel environmental exposure or stimuli that induce synaptic plasticity. Its messenger RNA (mRNA) is quickly transported to dendrites soon after synthesis for local translation by active synapses. Protein synthesis is a heavily- regulated process. It has been recently discovered that m6A RNA methylation, an epitranscriptomic modification, and m6A reader proteins (RNA binding proteins that recognize m6A and cause downstream functional consequences), play key roles in mRNA nuclear export, transport, localization, translation efficiency and stability. Although the specific significance of m6A RNA methylation in the nervous system is not well understood, using mice deficient in m6A or mice deficient in m6A readers, we have found that m6A RNA methylation plays a significant role in learning and memory. However, the link between m6A regulation of mRNA localization/translation and learning/memory is still unknown. We hypothesize that m6A methylation of mRNAs regulates the rates of protein synthesis from dendritically localized mRNAs and affects synaptic plasticity. As a first step to test our hypothesis, we propose to focus on Arc for the following reasons. We have discovered several m6A sites on Arc mRNA. Arc protein is synthesized locally in dendrites. Arc plays a significant role in synaptic plasticity. We will manipulate m6A levels in the Arc mRNA and determine how Arc localization and local protein synthesis will be affected by m6A and by stimuli that induce synaptic plasticity.
We propose to characterize the role of methylation of the human gene ARC/Arg3.1 which plays a key role in learning and memory and synaptic plasticity. These studies will have significant implications in neurological and psychiatric disorders.