F. M. Kirby Chair in Neural Repair and Protection
Director, Neuropsychopharmacology Center
NMDA receptors, mTOR signaling, synaptic plasticity, epigenetics, autism, Fragile X syndrome, schizophrenia, stroke, neuronal death.
There are four major lines of ongoing research in the Zukin lab.
First, we are studying RNA trafficking and targeting to dendrites and local protein synthesis in Fragile X syndrome. We found that mTOR signaling is overactivated in hippocampal neurons of Fragile X mice and causally related to aberrant synaptic plasticity. We also found that targeting of AMPAR mRNAs to synapses under basal conditions and in response to mGluR signaling is dysregulated in Fragile X neurons. We are using a combination of high resolution imaging of individual mRNA molecules (in collaboration with the Singer lab), molecular biology, and electrophysiology to examine AMPAR mRNA trafficking, local translation, synaptic plasticity and spine structure in Fragile X mice. Objectives are to identify novel signaling pathways that play a role in synaptic dysfunction. We believe that understanding the mechanisms responsible for abnormal function at the synapse will advance novel therapeutic strategies to ameliorate cognitive deficits in Fragile X syndrome and unlock doors for treating other autism spectrum disorders.
A second area of interest is that of the molecular and cellular mechanisms that regulate N-methyl-D-aspartate-type glutamate receptor (NMDA receptor) expression at synapses in the brain. We discovered that the switch in NMDA receptor phenotype at hippocampal synapses during normal brain development is regulated by epigenetics in an experience-dependent manner. In normal brain, the gene silencing transcription factor REST is activated during a brief window of time in differentiated neurons of the hippocampus, a brain center implicated in learning and memory, and drives the switch from immature to mature NMDA receptors. Remarkably, depriving pups of maternal access for brief periods of time during the first postnatal week prevents activation of REST and epigenetic modifications essential to acquisition of mature NMDA receptors and normal brain development. These findings have striking implications for treatment of anxiety, post-traumatic stress and other disorders associated with early maternal separation. New questions are: What is the mechanism by which REST is activated during brain development? Do other forms of stress regulate the switch in NMDA receptors? What are the consequences of blocking the switch? 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. NMDA receptor dysregulation is implicated in Alzheimer’s disease, Huntington's disease, AIDS dementia, stroke and schizophrenia.
Third, we are studying the molecular and cellular mechanisms that underlie the neuronal death associated with stroke and epilepsy. We discovered that neuronal insults activate REST in selectively vulnerable adult hippocampal neurons. Upon activation, REST orchestrates epigenetic reprogramming of neuronal genes in differentiated neurons. We further showed that prolonged activation of REST is causally related to neuronal death in a clinically-relevant model of ischemic stroke. A key downstream target of REST in insulted CA1 neurons is the gene encoding the AMPA receptor subunit GluA2. This is of interest because the GluA2 subunit governs calcium permeability, channel conductance and AMPA receptor trafficking to and from synaptic sites. GluA2-lacking AMPA receptors are highly permeable to calcium and zinc, which rise to toxic levels in insulted neurons. Objectives are: 1) to understand how REST is activated in insulted neurons; 2) to examine epigenome-wide dysregulation of REST targets in stroke, Huntington's disease and Alzheimer's disease; and 3) to 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 fourth area of interest is that of estrogen neuroprotection in animal models of stroke, including global ischemia. Recently, we found that long-term treatment with estrogen at physiological levels ameliorates death of hippocampal neurons and cognitive deficits associated with global ischemia. We showed that ischemia and estrogen act synergistically to activate the transcription factor STAT3 and promote transcription of survivin, an inhibitor of apoptosis protein and gene target of STAT3, in insulted CA1 neurons. In experiments in which we employ direct delivery of shRNA constructs into the hippocampal CA1 of living animals, we found that STAT3 and survivin are essential to estrogen neuroprotection. These findings identify STAT3 and survivin as therapeutic targets in a clinically-relevant model of stroke. Objectives are to identify 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.
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.
(From a total of 184 peer-reviewed papers and 41 book chapters)
Huber KM, Klann E, Costa-Mattioli M, Zukin RS. Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism. J Neurosci. 35:13836-42, 2015. PMID: 26468183
Tamminga CA, Zukin RS. Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology. Neuroscience. 309:233-42, 2015. PMID: 26211447
Choi CH, Schoenfeld BP, Weisz ED, Bell AJ, Chambers DB, Hinchey J, Choi RJ, Hinchey P, Kollaros M, Gertner MJ, Ferrick NJ, Terlizzi AM, Yohn N, Koenigsberg E, Liebelt DA, Zukin RS, Woo NH, Tranfaglia MR, Louneva N, Arnold SE, Siegel SJ, Bolduc FV, McDonald TV, Jongens TA, McBride SM. PDE-4 inhibiton rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome. J Neurosci 35:396-408, 2015. PMID: 25568131
Takeuchi K*, Yang Y*, Takayasu Y, Gertner M, Hwang J-Y, Aromolaran KA, Bennett MVL, Zukin RS. Estradiol pretreatment ameliorates impaired synaptic plasticity at synapses of insulted CA1 neurons after transient global ischemia. Brain Res. pii: S0006-8993(14)01563-7, 2015. PMID: 25463028
Hwang JY, Kaneko N, Noh KM, Pontarelli F, Zukin RS. The Gene Silencing Transcription Factor REST represses miR-132 expression in Hippocampal Neurons Destined to Die. J Mol Biol 426:3454-66, 2014. PMID: 25108103
Kaneko N, Hwang J-Y, Gertner M, Pontarelli F, Zukin RS. Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death. J Neurosci, 34:6030-9, 2014. PMID: 24760862
Murphy J*, Stein IS*, Lau GC, Peixoto R, Kaneko N, Aromolaran K, Saulnier J, Sabatini BL, Hell JW, Zukin RS. Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. J Neurosci, 34:869-879, 2014. PMID: 24431445
Sehara Y, Sawicka K, Hwang JY, Latuszek-Barrantes A, Etgen AM, Zukin RS. Survivin is a transcriptional target of STAT3 critical to estradiol neuroprotection in global ischemia. J Neurosci 33:12364-74, 2013. PMID: 23884942
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 110:4738-43, 2013. PMID: 23487788
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
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
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
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
Sawicka K, Zukin RS. Dysregulation of mTOR signaling in neuropsychiatric disorders: therapeutic implications. Neuropsychopharmacology 37:305-6, 2012. PMID: 22157871
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
Peek 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
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
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 69:780-92, 2011. PMID: 21338886
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
Philpot BD, Zukin RS. Synapse-specific metaplasticity: to be silenced is not to silence 2B. Neuron 66:814-6, 2010. PMID: 20620866
Zukin RS. Eradicating the mediators of neuronal death with a fine-tooth comb. Sci Signal 3:pe20, 2010. PMID: 20530801
Wang DO, Martin KC, Zukin RS. Spatially-restricted regulation of gene expression in neurons. Trends Neurosci 33:173-82, 2010. PMID: 20303187
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
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
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
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
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 30:126-34, 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, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, Lin Y, Bennett MV, Yuste R, Castillo PE, Zukin RS. 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 USA 102:12230-5, 2005. PMID: 16093311
Lan J-Y, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, Zheng X, Bennett MVL, Zukin RS. Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 4: 382-390, 2001. PMID: 11276228
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