Grant: Operating Grant - PA: INMHA (bridge funding)

Inappropriate noradrenergic neurotransmission is correlated with several cognitive and affective disorders, such as Alzheimer's disease, post-traumatic stress disorder (PTSD), attention deficit disorder, and depression. Increased plasma norepinephrine (NE) is common in PTSD, and propranolol, a beta-adrenergic receptor (b-AR) blocker, can decrease future PTSD symptoms. Reduced noradrenergic activity is correlated with age-related memory dysfunction. Conversely, physiological activation of noradrenergic receptors can protect against neural injury, promote neurogenesis, and aid recovery from brain inflammation. Because memory enhancement is a primary goal of cognitive rehabilitation programs, a top research priority will continue to be the identification of molecular targets for boosting the endurance of memories and for treatment of cognitive disorders. This proposal focuses on the proteins eIF4E and CBP, two "master regulators" of translation and transcription. Viewed broadly, eIF4E dysregulation has been implicated in autism-like disorders of social cognition, whereas CBP is part of an array of epigenetic mechanisms that can contribute to the pathogenesis of several CNS/cognitive disorders, such as Rubinstein-Taybi syndrome , Angelman syndrome, fragile-X mental retardation, and Rett syndrome. Also, neurodegenerative disorders of aging, such as Alzheimer's disease, and neuropsychiatric disorders such as drug addiction, have been linked to dysfunctional epigenetic mechanisms. By studying how b-AR signaling may be linked to translation regulation by eIF4E and epigenetic control of gene expression by CBP during synaptic plasticity, this proposal may reveal new strategies for boosting brain plasticity and improving mental health.