Synaptic plasticity has been linked to the regulation of dendritic synthesis of proteins, whereby synaptic stimulation activates local translation of pre-existing mRNAs that are stored close to the synapse. Local protein synthesis at synapses can lead to long-lasting modification in synaptic strength and efficacy. A key unanswered question is how localized translation control occurs. Two features of control are apparent;there is long-term and constitutive silencing of translation but there is also rapid and inducible de-silencing of translation. This grant seeks to explore the mechanisms behind silencing/de-silencing. We are working with the assumption that some of this control is mediated by microRNAs. This remarkable class of non-coding RNAs repress the translation of mRNA transcripts, which contain miRNA-binding sites in their 3'untranslated regions. MicroRNAs located in dendrites are known to repress functionally important mRNAs, and derepress under certain conditions. Our goal is to understand how miRNAs lock up their target mRNAs, and how synaptic activities release their target mRNAs for translation. To this end, we have discovered that cells release targets when endocytosis occurs. Endosomes recruit repressed complexes to their limiting membranes, and as endosomes mature to late endosome stages, complexes are dissociated and turned over. This enables targets to be released.
The aims of the grant are to determine if activity-dependent endocytosis releases mRNAs from miRNA-mediated repression in a non-synaptic and synaptic neuronal model. If we uncover such a mechanism, it would advance understanding of synaptic plasticity. The significance to health is manifold. Understanding the molecular mechanisms that regulate synaptic plasticity is of paramount importance to decipher behavioral plasticity, how mental illness can disrupt it, and guide development of new therapeutic technologies.
MicroRNAs are regulators of gene expression, and their dysfunction is linked to diverse forms of neurological disorders. This project is to understand how microRNAs control protein translation in neurons, particularly in synapses. Their relationship to synaptic plasticity is of particular interest.