Memory is our most precious possession, yet we remain unable to prevent its loss in neurological diseases. Here we examine a fundamental property of memory, which is its dependence on rapid de novo protein synthesis, and identify pathways that contribute to normal memory and that underlie human memory loss. Dr. Worley's laboratory pioneered the discovery and analysis of cellular immediate early genes (IEGs) as effectors of protein synthesis-dependent memory, and has described mechanisms mediated by IEGs Arc, Homer 1a and NPTX2 at excitatory synapses that strengthen active synapses and weaken inactive synapses. Emerging concepts integrate their individual molecular and synaptic functions into a temporal program of sequential cellular and circuit adaptations that encode information. The process begins with Arc and Homer1a, which act cell-autonomously to control the synaptic expression of AMPA type glutamate receptors. A later process mediated by secreted NPTX2 acts non cell-autonomously to strengthen excitatory synapses on a specific class of inhibitory neurons that express parvalbumin. Studies from mouse models indicate that down regulation of NPTX2 results in increased neural activity that may occlude the ability of networks to encode information, as well as a propensity for activity-dependent pathology including seizures and A amyloid generation. Remarkably, aspects of this inhibitory network phase of information storage can be monitored in living human subjects. Secreted NPTX2 is detected in human CSF and is prominently down-regulated in neurological diseases in association with cognitive deterioration. We hypothesize that NPTX2 down-regulation provides a rational biomarker of cognitive status in human neurological disease and may be is causal for certain memory deficits. Basic studies will examine the unusual regulatory mechanisms that control NPTX2 expression and function, and identify processes that result in its down-regulation in human brain. We will also gain deeper insight into how IEGs, and NPTX2 in particular, contribute to memory using gain and loss of function approaches in in vivo models of activity-dependent network plasticity including hippocampal replay. Stable, long-term support will allow us to establish a multidisciplinary research program that leverages the strengths of the Neuroscience community at Johns Hopkins for basic studies, and the Clinical Departments of Neuropathology and Psychiatry at Johns Hopkins and Neurology at UC San Diego for translational aspects of disease research. These studies will establish a novel, rational, and translatable concept for why humans lose memory function in disease.
Rapid de novo mRNA and protein synthesis are required for memory. We have identified immediate early genes that mediate the de novo response and here will elucidate, molecular, cellular and network processes that underlie normal memory as well as cognitive failure in human neurological disease.
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