Director, Neuropsychopharmacology Center
F. M. Kirby Chair in Neural Repair and Protection
NMDA receptors, AMPA receptors, receptor trafficking, synaptic plasticity, epigenetics, stroke, neuronal death, autism, Fragile X syndrome, Alzheimer's disease
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 recently 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 data 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 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.
Takeuchi K, Gertner MJ, Zhou J, Parada LF, Bennett MVL, Zukin RS. Dysregulation of synaptic plasticity precedes morphological defects in a Pten conditional knockout mouse model of autism. Proc Natl Acad Sci USA. 2013 Mar 4. [Epub ahead of print]
Hwang JY, Aromolaran K, Zukin RS. Epigenetic mechanisms in stroke and epilepsy, Neuropsychopharmacology 38:167-82, 2013. PMID: 22892394
Rodenas-Ruano A, Chávez AE, Cossio MJ, Castillo PE, Zukin RS. REST-dependent epigenetic remodeling drives the developmental switch in synaptic NMDA receptors in vivo. Nat Neurosci 15:1382-90, 2012. PMID: 22960932
Udagawa, T, Swanger, SA, Takeuchi, K, Kim, JH, Nalavadi, V, Shin, J, Lorenz, LJ, Zukin RS, Bassell GJ, Richter, JD. Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Mol Cell 47:253-66, 2012. PMID: 22727665
Ofengeim D, Chen YB, Miyawaki T, Li H, Sacchetti S, Flannery RJ, Alavian KN, Pontarelli F, Roelofs BA, Hickman JA, Hardwick JM, Zukin RS, Jonas EA. N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death. Nat Neurosci 15:574-80, 2012. PMID: 22366758
Noh KM*, Hwang JY*, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MVL, Zukin RS. Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci USA 109:E962-71, 2012. PMID: 22371606
Sawicka K, Zukin RS. Dysregulation of mTOR signaling in neuropsychiatric disorders: therapeutic implications. Neuropsychopharmacology 37:305-6, 2012. PMID: 22157871
Hoeffer CA, Sanchez E, Hagerman RJ, Mu Y, Nguyen DV, Wong H, Whelan AM, Zukin RS, Klann E, Tassone F. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav 11:332-341, 2012. PMID: 22268788
Paek H, Hwang J-Y, Zukin RS, Hébert JM β-catenin-dependent FGF signaling maintains cell survival in the anterior embryonic head by countering Smad4. Dev Cell 20:689-99, 2011. PMID: 21571225
Jitsuki S, Takemoto K, Kawasaki T, Tada H, Takahashi A, Becamel C, Sano A, Yuzaki M, Zukin RS, Ziff EB, Kessels HW, Takahashi T. Serotonin mediates cross-modal reorganization of cortical circuits. Neuron 69:780-922011, 2011. PMID: 21338886
Nolt MJ, Lin Y, Hruska M, Murphy J, Sheffler-Colins SI, Kayser MS, Passer J, Bennett MVL, Zukin RS, Dalva M. EphB controls NMDAR function and synaptic targeting in a subunit-specific manner. J Neurosci 31:5353-64, 2011. PMID: 21471370
Brown TE, Lee BR, Mu P, Ferguson D, Dietz D, Ohnishi YN, Lin Y, Suska A, Ishikawa M, Huang YH, Shen H, Kalivas PW, Sorg BA, Zukin RS, Nestler EJ, Dong Y, Schlüter OM. A silent synapse-based mechanism for cocaine–induced locomotor sensitization. J Neurosci 31:8163-74, 2011. PMID: 21632938
Etgen AM, Jover-Mengual T, Zukin RS. Neuroprotective actions of estradiol and novel estrogen analogs in ischemia: translational implications. Front Neuroendocrinol 32:336-52, 2011. PMID: 21163293
Eugenin EA, King JE, Hazleton JE, Major EO, Bennett MV, Zukin RS, Berman JW. Differences in NMDA receptor expression during human development determine the response of neurons to HIV Tat neurotoxicity. Neurotox Res 19:138-48, 2011. PMID: 20094923
Takayasu Y, Kumari R*, Takeuchi K*, Bennett, MVL, Zukin RS, Francesconi A. Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses. Proc Nat Acad Sci USA 107:21778-83, 2010. PMID: 21098662
Liu Y, Formisano L, Savtchouk I, Takayasu Y, Szabò G, Zukin RS, Liu SQJ. A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPA receptor phenotype. Nat Neurosci 13:223-31, 2010. PMID: 20037575
Sharma A, Hoeffer C, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS. Dysregulation of mTOR signaling in the Fragile X mouse. J Neurosci 30:694-702, 2010. PMID: 20071534
Lau CG, Takayasu Y, Rodenas-Ruano A, Paternain AV, Lerma J, Bennett MVL, Zukin RS. SNAP-25 is a target of PKC phosphorylation critical to NMDA receptor trafficking. J Neurosci 30:242-54, 2010. PMID: 20053906
Wang DO,Martin KC, Zukin RS Spatially-restricted regulation of gene expression in neurons. Trends Neurosci 33:173-82, 2010. PMID: 20303187.
Stetler RA, Gao Y. Zukin RS, Vosler PS, Zhang L, Zhang F, Cao G, Bennett MVL, Chen J. Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. Proc Natl Acad Sci USA 107:3204-9, 2010. PMID: 20133634.
Jover-Mengual T, Latuszek-Barrantes A, Alborch E, Zukin RS, Etgen AM. Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway. Brain Res 1321:1-12, 2010 PMID: 20114038.
Lebesgue D, Traub M, De Butte-Smith M, Chen C, Zukin RS, Kelly MJ, Etgen AM. Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged rats PLoS ONE 8:28642, 2010. PMID: 20062809
Zukin RS, Richter JD, Bagni C Signals, synapses, and synthesis: how new proteins control plasticity. Front Neural Circuits 3:14, 2009. PMID: 19838324
Huang YH, Lin Y, Mu P, Lee BR, Brown TE, Wayman G, Marie H, Liu W, Yan Z, Sorg BA, Schluter OM, Zukin RS, Dong Y. In vivo cocaine experience generates nascent synapses. Neuron 63:40-7, 2009. PMID: 19607791
Lebesgue D, Chevaleyre V, Zukin RS, Etgen AM. Estradiol rescues neurons from global ischemia-induced cell death: Multiple cellular pathways of neuroprotection. Steroids 74:555-61, 2009. PMID: 19428444
Miyawaki T*, Ofengeim D*, Noh K-M, Latuszek-Barrantes A, Hemmings BA, Follenzi A, Zukin RS. The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. Nat Neurosci 12:618-26, 2009. PMID: 19349976
Francesconi A, Kumari R, Zukin RS. Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway. J Neurosci 29:3590-3602, 2009. PMID: 19295163
Francesconi A, Kumari R, Zukin RS. Proteomic analysis reveals novel binding partners of metabotropic glutamate receptor 1. J Neurochem 108:1515-1525, 2009. PMID: 19183249
Yang Y*, Takeuchi K*, Rodenas-Ruano A, Takayasu Y, Bennett MVL, Zukin RS. Developmental switch in requirement for PKA RII-b in NMDA receptor-dependent synaptic plasticity at Schaffer collateral to CA1 pyramidal cell synapses. Neuropharmacology 56:56-65, 2009. PMID: 18789341
Miyawaki T, Mashiko T, Ofengeim D, Flannery R, Noh K-M, Bennett MVL,Zukin RS, Jonas EA. Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage and large channel activity in mitochondria of postischemic hippocampal neurons. Proc Natl Acad Sci USA 105:4892-4897, 2008. PMID: 18347331
Huang YH et al. CREB modulates the functional output of nucleus accumbens neurons: A critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors. J Biol Chem 283:2751-60, 2008. PMID: 19607791
Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 8:57-64, 2008. PMID: 18206423
Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413-26, 2007. PMID: 17514195
Formisano L, Noh K-M, Miyawaki T, Mashiko T, Bennett MVL, Zukin RS. Ischemic insults promote epigenetic reprogramming of µ opioid receptor expression in hippocampal neurons, Proc Natl Acad Sci USA 104:4170-5, 2007. PMID: 17360495
Liu, S-QJ, Zukin RS. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci 126-34, 2007. PMID: 17275103
Grooms SY*, Noh K-M*, Regis R, Bassell GJ, Bryan MK, Carroll RC, Zukin RS. Activity bidirectionally regulates AMPAR mRNA abundance in dendrites of hippocampal neurons. J Neurosci 26:8339-51, 2006. PMID: 16899729
Skeberdis VA et al. PKA regulates calcium permeability of NMDA receptors. Nat Neurosci 9:501-10, 2006. PMID: 16531999
Noh K-M, Yokota H, Mashiko T, Castillo PE, Zukin RS, Bennett MV. Blockade of Calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc Natl Acad Sci USA102:12230-5, 2005. PMID: 16093311
More Information About Dr. R. Suzanne Zukin
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Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South , Room 603
Bronx, NY 10461