Grant: Operating Grant

Synthesis of new proteins, a process called translation, is necessary for persistent changes in synaptic strength that underlie learning and memory. Learning and memory impairments are important aspects of some of the most common and debilitating neurological disorders, such as Alzheimer's disease and related dementia, as well as in genetic brain disorders such as mental retardation and intellectual deficiency. Moreover, dysregulation of translation in neurons has been linked to synaptic dysfunction and autism spectrum disorders. Translation of mRNA into protein is also regulated at the level of synapses. A major site of regulation of translation initiation is by eIF4E control of the eIF4F complex which brings together the mRNA and ribosome. We found that this regulatory site controls long-term synaptic changes underlying learning and memory, and more recently that its dysregulation in mice leads to synaptic aberrations and autistic-like behavioral phenotypes. However, the activity-dependent mechanisms by which eIF4E controls translation and synaptic function in the different types of neurons in the hippocampal network remain poorly understood. We propose to build on our previous work and identify the molecular and cellular mechanisms by which eIF4E controls translation and synaptic function in specific hippocampal cell types leading to memory formation in normal conditions, and how dysregulation leads to autism. Identifying and elucidating these cellular and molecular mechanisms are the first step in developing new approaches to tackle the important health problems associated with autism spectrum disorders and neurological disorders with memory impairments.