R. Suzanne Zukin

NMDA and AMPA receptors in synaptic plasticity and neuronal death

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 hope to identify the molecular target(s) for PKC phosphorylation. We have also found that calcium influx through NMDA receptors in dendritic spines is under the control of the cAMP/PKA signaling cascade. As a consequence, PKA signaling affects induction of several forms of longterm potentiation in the hippocampus. Questions are: Is PKA modulation of calcium influx through NMDA receptors developmentally regulated? What is the molecular target of PKA? 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, 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. The substantial delay between neuronal insult and death suggests a role for transcriptional changes. We have found that ischemia activates REST and that REST is critical to death of CA1 neurons. The AMPA receptor GluR2 gene is a target of REST. Silencing of GluR2 promotes assembly of calcium-permeable AMPARs and cell death. Our interest stems from the known role of AMPA receptors in neuronal death arising in stroke, epilepsy, ALS and Alzheimer's disease. Objectives are to identify new REST targets, clarify how REST is activated and develop novel strategies of neuroprotection.

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 ERα and insulin-like growth factor-I (IGF-I) and ERK/MAP kinase signaling to protect cells. A downstream target is the transcription factor CREB, which promotes expression of anti-apoptotic proteins such as Bcl-2. Objectives are to identify mechanisms by which estrogen rescues neurons. Currents studies address the forkhead and caspase death cascades. Our interest stems from data that estrogen reduces the risk of cardiac arrest and stroke in humans.

A fourth area of interest is that of RNA trafficking and local protein synthesis in Fragile X. Recently, we found that AMPAR mRNAs are targeted to synapses and that mGluR activation promotes targeting of AMPAR mRNAs to synaptic sites. We are using a combination of molecular biological and live-cell imaging techniques to examine dysregulation of AMPAR mRNA trafficking and local translation in the Fragile X mouse. 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 synaptic plasticity, molecular and cognitive impairments in Fragile X. Experiments will address alterations and dysregulation of 1) synaptic plasticity; 2) AMPAR trafficking; and 3) cognition in Fragile X mice and the ability of specific therapeutic strategies to ameliorate these deficits.

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