 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
R. Suzanne ZukinF.M. Kirby Professor of Neural Repair and Protection Director, Neuropsychopharmacology Center Professor Kennedy Center Lab Webpage: nmda.aecom.yu.edu
|
|
|
There are four major lines of ongoing research in the Zukin lab. First, we are studying the molecular and cellular mechanisms that regulate the trafficking of N-methyl-D-aspartate-type glutamate receptors (NMDA receptors) to and from the synapse. We have found that protein kinase C (PKC) regulates cellular trafficking and gating of NMDA receptors. We identified the SNARE protein SNAP-25 as the molecular target of PKC phosphorylation critical to receptor insertion. We discovered that calcium influx through NMDA receptors in dendritic spines is under the control of the cAMP/PKA signaling cascade. This phenomenon is developmentally regulated. As a consequence, PKA signaling affects induction of several forms of long term potentiation in the hippocampus. PKA modulation of calcium influx through NMDA receptors is developmentally regulated. New questions are: What is the molecular target of PKA? Is the switch in NMDA receptor subtype during brain development regulated by epigenetic mechanisms? Our interest stems from the fact that NMDA receptors play a central role in cognitive functions such as learning and memory, synaptic plasticity and formation of neural circuitry. NMDAR dysregulation is implicated in Alzheimer’s disease, Huntington's disease, AIDS dementia, stroke and schizophrenia. Second, we are studying the molecular and cellular mechanisms that underlie the neuronal death associated with stroke and epilepsy. The gene silencing transcription factor REST is widely expressed during embryogenesis and plays a strategic role in neural differentiation. In progenitor cells, REST silences neuron-specific genes. As progenitors differentiate, REST downregulation is essential for elaboration of the neural phenotype. Global ischemia, arising due to cardiac arrest, induces selective, delayed death of hippocampal neurons. We discovered that ischemia activates REST in selectively vulnerable hippocampal neurons and that REST is critical to death of CA1 neurons. The AMPA receptor GluR2 subunit is a target of REST. Silencing of GluR2 leads to assembly of AMPARs that are permeable to calcium and are causally related neuronal death. We have shown REST-dependent epigenetic reprogramming in adult neurons subjected to ischemia. Objectives are: 1) examine epigenome-wide dysregulation of REST targets in stroke, Huntington's disease and Alzheimer's disease 2) understand how REST is activated in insulted neurons and 3) identify novel strategies to protect the human brain from neurodegeneration. Our interest stems from the known role of AMPA receptors in neuronal death arising in stroke, epilepsy, ALS and spinal cord injury. A third area of interest is that of estrogen neuroprotection in animal models of stroke, including global ischemia. Recently, we (together with the Etgen lab) have found that long-term treatment with estrogen at physiological levels ameliorates death of hippocampal neurons and cognitive deficits in animals. We also found that estrogens act via the estrogen receptor ERalpha and insulin-like growth factor-I (IGF-I) and ERK/MAP kinase signaling to protect cells. Critical players are CREB, which promotes expression of anti-apoptotic proteins such as Bcl-2, STAT and JAK. Objectives are to identify transcription-dependent and epigenetic mechanisms by which estrogen rescues neurons. Our interest stems from findings that estrogen reduces the risk of cardiac arrest and stroke in animal models. A fourth area of interest is that of RNA trafficking and local protein synthesis in Fragile X. Recently, we found that mTOR signaling is overactivated in Fragile mice. We showed that dysregulation of mTOR is related to impaired synaptic plasticity in these mice. We also found that targeting of AMPAR mRNAs to synapses and regulation of RNA transport by mGluR signaling mRNAs are dysregulated in Fragile X neurons. We are using a combination of molecular biological and live-cell imaging techniques to examine dysregulation of AMPAR mRNA trafficking and local translation in Fragile X mice. Understanding the mechanisms underlying dysregulation of mGluR-dependent synaptic plasticity could help in the development of novel therapeutic strategies to ameliorate cognitive deficits in Fragile X Syndrome. An objective is to develop novel therapeutic strategies for amelioration of molecular and cognitive defects in Fragile X. Studies address dysregulation of mTOR signaling, synaptic plasticity and cognition in Fragile X and discovery of novel therapeutic strategies to ameliorate this debilitating human disorder. Positions for graduate students and post-doctoral fellows are available in all four areas of the laboratory's research. Independent researchers and ideas are welcome, while well-defined and achievable projects are waiting for motivated, young investigators. Selected Publications
|
||
