A. SIGNIFICANCE: Lack of knowledge of the key molecular players and signaling pathways is a critical barrier to the progress of understanding the role of new protein synthesis in specific components of neural circuitry for establishing long-term memories. The proposed project addresses this important problem by employing a multidisciplinary approach in which we systematically combine tools of imaging, state of the art genomics and bioinformatics, molecular biology, functional analysis and electrophysiology. The proposed research is highly significant due to the following six major reasons: (1) Translation is affected in several neurodegenerative disorders. Several studies have shown that alterations in diverse range of components of protein
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Mutations in any of the genes for the translation initiation factor eiF2B subunits, EIF2B1–5, lead to a severe autosomal recessive neuro-degenerative disorder termed ‘leukoencephalopathy with vanishing white matter or childhood ataxia with central hypomyelination (Knaap et al., 2002). (2) Manipulation of translation to develop novel therapeutics for Post-traumatic Stress Disorder (PTSD). Recent studies have shown that inhibition of translation might be beneficial for PTSD (Li et al., 2013; Yang et al., 2011; Cohen et al., 2006: Nader et al., 2000). (3) Novel insights into neuronal asymmetry, compartmentalization of signaling. It has been well established that neurons are highly polarized cells characterized by differential localization of proteins and mRNAs in different subcellular components. It is also shown that somatic and synaptic translation has a differential role in initiation and maintenance of …show more content…
Experiments proposed in this study will bring insights into whether translation is coordinated in the pre and postsynaptic neurons and the molecular substrates of translation. (6) Identification of novel regulators of synaptic plasticity. Our systematic analysis of translation in neuronal compartments during LTM will likely identify key regulators of synaptic plasticity and LTM. It is important to recognize that many concepts that are central to our overall understanding of learning and memory were established using Aplysia. For instance, the role of the cAMP signaling system, or branch-specific storage of memories discovered in Aplysia has also been shown to be important in Drosophila and the mouse [5]. Therefore, it is expected that contributions of the proposed studies will be conserved in mammals. Positive results would offer additional new insights into the mechanisms of memory storage and will have a major conceptual impact in the field. To our knowledge, such studies on LTM have not been reported in any system to date. Thus, the proposed research is groundbreaking a new area that must greatly influence learning and
Mutations in any of the genes for the translation initiation factor eiF2B subunits, EIF2B1–5, lead to a severe autosomal recessive neuro-degenerative disorder termed ‘leukoencephalopathy with vanishing white matter or childhood ataxia with central hypomyelination (Knaap et al., 2002). (2) Manipulation of translation to develop novel therapeutics for Post-traumatic Stress Disorder (PTSD). Recent studies have shown that inhibition of translation might be beneficial for PTSD (Li et al., 2013; Yang et al., 2011; Cohen et al., 2006: Nader et al., 2000). (3) Novel insights into neuronal asymmetry, compartmentalization of signaling. It has been well established that neurons are highly polarized cells characterized by differential localization of proteins and mRNAs in different subcellular components. It is also shown that somatic and synaptic translation has a differential role in initiation and maintenance of …show more content…
Experiments proposed in this study will bring insights into whether translation is coordinated in the pre and postsynaptic neurons and the molecular substrates of translation. (6) Identification of novel regulators of synaptic plasticity. Our systematic analysis of translation in neuronal compartments during LTM will likely identify key regulators of synaptic plasticity and LTM. It is important to recognize that many concepts that are central to our overall understanding of learning and memory were established using Aplysia. For instance, the role of the cAMP signaling system, or branch-specific storage of memories discovered in Aplysia has also been shown to be important in Drosophila and the mouse [5]. Therefore, it is expected that contributions of the proposed studies will be conserved in mammals. Positive results would offer additional new insights into the mechanisms of memory storage and will have a major conceptual impact in the field. To our knowledge, such studies on LTM have not been reported in any system to date. Thus, the proposed research is groundbreaking a new area that must greatly influence learning and