Synaptic plasticity describes the specific modification of synaptic connections in response to neuronal experience and is widely held as a cellular substrate of memory. Numerous studies have demonstrated that de novo protein synthesis is essential for stabilizing persistent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). However, there are two modes of translation in neurons that can contribute to the protein synthesis underlying these processes. The more common and well-studied mode is canonical or cap-dependent translation, which initiates when a multi-protein complex of translation initiation factors bind the 5'cap of eukaryotic mRNAs. Protein synthesis can also occur through a non- canonical pathway that initiates translation with a different set of factors from an internal ribosome entry site (IRES) in the mRNA. Very little is known about the role of this non-canonical pathway during normal physiological activity in neurons. However, previous work and new preliminary data from our lab suggests that this translation pathway may play a role in persistent forms of synaptic plasticity. The goal of the proposed research is to understand how non-canonical translation is involved specifically in a protein synthesis- dependent form of LTD mediated by metabotropic glutamate receptors (mGluR) in the hippocampus. I will use a combination of targeted viral and pharmacological manipulations with reporter activity assays, image analysis and proteomics to test the central hypothesis that non-canonical translation is actively utilized to support mGluR-LTD in the hippocampus.
The specific aim i s to characterize how non-canonical translation is temporally and spatially regulated following hippocampal mGluR-LTD. This work is significant because it addresses a major gap in our knowledge about activity-dependent regulation of protein synthesis during synaptic plasticity by providing insight into non-canonical mechanisms of translation. A better understanding of the neurobiological events that underlie synaptic plasticity will likely aid the development of new agents or strategies for improving memory function or weakening memories, which has important clinical implications.
The proposed research is relevant to public health because it aims to refine our understanding of the synaptic and molecular mechanisms that underlie normal memory function and how alterations in these processes may lead to neurological diseases and psychiatric disorders with cognitive impairments. By identifying specific molecular pathways that may be involved, this work can aid the development of new treatments for enhancing cognitive capacity in neurodegenerative disorders like Alzheimer's disease and for weakening pathological memories in conditions such as post-traumatic stress disorder (PTSD) and drug addiction.
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