Paul Worley MD
Professor of Neuroscience
Professor of Neuroscience
Arc is an immediate early gene involved in synaptic plasticity, learning and memory. Arc mRNA is rapidly transcribed and targeted to dendrites of neurons as they engage in information processing and storage. Arc protein induction is required for both late-phase LTP and spatial learning. Despite these intriguing associations with plasticity, Arc’s function remains enigmatic. Our lab has recently found that Arc regulates AMPA receptor trafficking by interacting with the endocytic machinery. These observations provide a molecular basis for understanding Arc’s function, and suggest a model in which dendritically localized Arc protein synthesis can modulate synaptic properties. The picture above shows Arc(red) and bassoon (green)staining in a 4 week old Hippocampal Neuron. Arc co-localizes with bassoon, which is a presynaptic marker.
The Worley lab studies the molecular basis of memory consolidation, and how this process is disrupted in human diseases including drug addiction, schizophrenia, and Alzheimer’s disease. Our focus is on a small set of genes whose mRNAs are rapidly transcribed as neurons process information, and whose protein products modify the strength of synaptic connections to enhance the formation of ensembles of neurons linked to experience (engrams). Currently, we propose these processes drive a cell cycle-like progression that begins with cell-autonomous events in pyramidal neurons that weaken inactive synapses while preserving the strength of active synapses. Foundational molecular events include the rapid de novotranslation of proteins within dendrites, cooperative interactions with neuromodulator signaling to activate mTORC1 signaling, and activation of metabotropic glutamate receptors to bidirectionally control synaptic strength. Hours later, these processes are joined by a cell non-autonomous process that strengthens network specific excitatory drive of fast-spiking inhibitory neurons. This latter process is required for neural rhythmicity important for cognition, and to rebalance excitation-inhibition to prevent epilepsy or excitotoxicity. Building on collaborations within the Hopkins community, we are examining each of these processes as potential mechanisms of cognitive or addictive disease using best available basic approaches including structural biology, transcription analysis, signaling and pathway analysis, brain slice electrophysiology, in vivoimaging in awake rodents, and behavior. For example, we can detect key molecules, such as NPTX2, in postmortem human brain and cerebrospinal fluid of living human subjects, and studies have revealed strong associations in Alzheimer’s disease with cognitive performance, regional brain connectivity, and disease progression. Based on this emerging work, we hypothesize that the memory consolidation process is central to an understanding of brain disorders, and in pathological conditions may become a driver of disease progression.