We are particularly interested in the elucidation of the protein machinery at the synapse and the basic cell biological processes that mediate long-term storage of information. In addition, we are investigating how these process go awry in neurodevelopmental disorders such as Angelman Syndrome and in cognitive decline during aging.T he overall goal of our research program is to investigate the role of activity-dependent processes, and the requisite gene programs, involved in synaptic plasticity and how these processes go awry in neurological disorders.
It has been known since the 1960s that new protein synthesis is required for stabile memory, yet it remains unclear how and why. Neural circuits are refined during development through activity-dependent gene and protein expression. Similar macromolecular synthesis is essential for long-term forms of synaptic plasticity such as long-term potentiation (LTP) and depression (LTD). Efforts to identify genes that underlie transcription-dependent plasticity have revealed a set of immediate early genes (IEGs) that target to excitatory synapses. Many of these IEGs have critical roles in synaptic function and plasticity, and have also been implicated in various neurological disorders. Among brain IEGs identified to date, Arc is the most tightly coupled to behavioral encoding of information in neuronal circuits.
Mice that lack Arc are profoundly deficient in long-term memory consolidation and in both synaptic and experience-dependent plasticity. Arc expression is exquisitely fined tuned; transcription is rapid and activity-dependent, mRNA is transported to dendrites and protein is locally translated in response to various signaling pathways. Arc protein regulates the AMPA type glutamate receptor at excitatory synapses. Why is Arc so tightly regulated? How does Arc render memories stabile? What is Arc’s precise synaptic function? The uniqueness of Arc is that it allows one to study mechanisms of neural circuit development and refinement at both the synaptic and circuit level, providing insight in how to bridge molecules and behavior.
Project 1: Investigate the role of Arc in experience-dependent plasticity in neural circuits
The major goal of this project is to investigate the role of Arc in experience-dependent plasticity at the single cell level using in vivo two-photon calcium imaging and the use of molecular manipulations that probe Arc’s function in an intact neuronal circuit.
In work published in PNAS, we showed that Arc controls the critical period of visual cortex plasticity. Arc induction declines with age and increasing Arc expression in adult visual cortex is sufficient to restore juvenile-like plasticity.
Project 2: Investigate the role of Arc in neurological disorders
LTD is enhanced in FMRP KO mice, and this enhancement is abolished by removing Arc protein from FMRP KO mice, suggesting that some of the plasticity and cognitive phenotypes observed in FXS are possibly due to disruption of Arc expression. In recent findings, Arc was found to be a direct target of the ubiquitin ligase Ube3A, which is a gene that when mutated causes a debilitating neurological disorder called Angelman syndrome (AS) and has also recently been implicated in autism spectrum disorders. Loss of Ube3A activity causes an increase in Arc and a concomitant decrease in synaptic AMPARs that is Arc-dependent. Moreover, Ube3a mutant mice have severe deficits in experience-dependent and synaptic plasticity in V1 that are strikingly similar to the phenotypes found in Arc KO mice. Taken together, these findings suggest that over-expression or dysregulation of Arc protein levels is potentially a causative factor in a number of neurological disorders. Since Arc is a critical effector molecule, downstream of many signaling pathways, dysfunction of Arc could be a nexus point for synaptic dysfunction in diseases of cognition. Due to the dynamic nature of Arc expression, the challenge will be to devise tools that will allow finely tuned manipulation of Arc expression.
The ultimate hope is that these in vivo assays will better reflect disease outcomes in human patients and provide a platform to evaluate therapeutic targets. This approach can be generalized to most other disorders where there is an established mouse model and known/suspected synaptic defects such as in Alzheimer’s disease, Fragile X, Angelman and Rett syndromes, which could shed insight into general mechanisms of autism, mental retardation and neurodegeneration.
Project 3: The role of Arc in intercellular trafficking of RNA and protein
There are a number of fundamental cell biological questions that need to be addressed: What cargo does Arc transfer cell-to-cell? Which cells take up Arc vesicles? Where and when does Arc form capsids in neurons? Moreover, there are dozens of putative animal genes that contain similar Gag-like domains that could confer related viral properties. The ability to form capsids and transfer genetic material may not be unique to Arc. Thus, our work may have uncovered a new mode of cellular communication derived from the repurposing of retroviral biology. The lab’s future work will shed light on the evolutionary origins of cognition and the cell biology underlying information storage in the brain.