Translational control of gene expression is a key mechanism in the experience-dependent long-term modulation of neuronal form and function. It is hypothesized that regulatory RNAs play essential roles in the implementation of this mechanism. Synapto-dendritic BC RNAs control neuronal protein synthesis by targeting the translation mechanism through interactions with eukaryotic initiation factors (eIFs). The resulting translational repression is an important component in the molecular management of synaptic strength as lack of BC1 RNA in animal models causes excessive protein synthesis, neuronal hyperexcitability, and a propensity for epileptogenic responses. The elucidation of molecular mechanisms of BC RNA control will continue to constitute a major emphasis of the project Translational control in neurons. However, while molecular mechanisms are fundamental underpinnings of translational control pathways, it will now become important to move the investigation to the next level by addressing significant open issues that have come to the fore as a result of previous advances. Three fundamental questions are commanding highest priority at this time: (i) how is BC RNA translational control reversibly modulated, (ii) how do neurons implement such modulation in an activity- dependent manner, and (iii) how does this form of molecular regulation impact neuronal function and plasticity? To address these questions, a Research Plan will be implemented in three Specific Aims.
The first Aim will test the hypothesis that the phosphorylation status of eIF4B is a determinant of BC RNA binding and translational repression competence. It is further hypothesized that in neurons, BC RNA translational control is subject to activity-dependent modulation via eIF4B phosphorylation changes. This mechanism will be functionally dissected in Aim 2.
Aim 3 will be directed at the role of the BC RNA - eIF4B translational control mechanism in neuronal function, excitability, and plasticity. It will be the long-term goal of the planned project to arrive at a molecular-mechanistic understanding of how reversible, activity-dependent translational control is implemented by synapto-dendritic BC RNAs, and how such control supports elemental forms of neuronal functionality.
Mechanisms of translational control are directly relevant to neuronal plasticity and, consequently, to higher brain functions that rely on such plasticity. NS046769-funded work has established that BC RNA translational regulation is essential for the maintenance of neuronal excitation-repression balances. Disturbances of this balance may cause neuronal hyperexcitability, a propensity for epileptogenic responses, and autism-like behavioral alterations.
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