Active Research Projects
The persistence of memory in the hippocampus: the Wnt-GSK3-mTOR axis
The hippocampus is intimately involved in encoding and storing episodic memories. These functions are thought to reflect long-lasting forms of synaptic plasticity; for example, hippocampus-mediated learning results in increased efficiency of signaling at a population of excitatory synapses. For such synaptic change to persist for more than a few hours, plasticity proteins must be synthesized from mRNAs that reside within the dendrites of hippocampal neurons. We have shown that translation regulator mammalian target of rapamycin (mTOR) plays a central role in the neuronal decision to translate these mRNAs and express long-term plasticity, thus serving to discriminate (at the molecular level) high-saliency events from weaker ones. This on-demand increase in mTOR activity is consistent with the suppression of mTOR under resting conditions, which would be necessary to prevent aberrant formation of memories for insignificant events. Currently, we are investigating the role of the constitutively active enzyme glycogen synthetase 3 (GSK3) in this suppression of mTOR, and its relief by secreted Wnt proteins. Through this work, we expect to characterize the decision network, upstream and downstream of Wnt secretion, that integrates inputs from transmitters and voltage-gated channels to determine mTOR activity and the translational capacity of the neuron.
The selection of plasticity mRNAs for translation
The mTOR-mediated increase in the neuron’s translational capacity is one important determinant of plasticity protein synthesis for expressing stable synaptic plasticity; another key regulated process is the selection of the mRNAs to be translated. We have found that the identity of the newly synthesized plasticity proteins depends on the direction of synaptic change: stimulation that increases synaptic efficiency causes specific mRNAs to be translated that are not among those translated in response to stimulation that depresses synaptic efficiency. The stimulation characteristic that is most important in dictating which mRNAs to translate is its frequency, and we are investigating the signaling network encodes stimulation frequency to select among the many species of dendritic mRNAs that otherwise are in a translationally repressed state. This project is expected to reveal fundamental mechanisms for plasticity-related protein synthesis in the brain.
Non-motor aspects of Parkinson’s disease: the role of LRRK2
In addition to the prominent motor disorder that is the hallmark of Parkinson’s disease (PD), other common symptoms are related to dysfunctions in other brain functions. These include sensory disorders, depression, and dementia. To better understand the basis for PD-associated dementia in particular, we are investigating PD-linked mutations in the protein kinase LRRK2 and their effect on the electrophysiological characteristics of the hippocampus, in collaboration with Zhenyu Yue (http://icahn.mssm.edu/research/labs/yue-laboratory). LRRK2 is highly expressed in the hippocampus, and we are especially interested in abnormal hippocampal synaptic plasticity in mice that harbor relevant LRRK2 mutations. We expect this project to establish a hippocampal phenotype that may underlie some of the cognitive deficits of PD, and at the same time shed light on the normal function of LRRK2 in synaptic plasticity.
Robert Blitzer, PhD
Icahn Medical Institute Floor 12 Room 12-52A (Office)
1425 Madison Avenue
New York, NY 10029