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.
Research in our laboratory addresses molecular and cellular mechanisms underlying neuronal death. A particular focus centers on epigenetic mechanisms that underlie neuronal death in animal models of stroke, global ischemia, epilepsy and Alzheimer’s disease. We are studying the role of the gene silencing transcription factor REST and REST-dependent epigenetic remodeling of synaptic proteins. We found that REST is activated in response to neuronal insults such as global ischemia and orchestrates epigenetic remodeling of synaptic AMPA receptors. This, in turn, silences expression of the AMPA receptor subunit GluA2 and a switch from Ca2+-impermeable to Ca2+-permeable AMPA receptors at hippocampal synapses. We found that REST is causally related to the switch in AMPA receptor phenotype and neuronal death. Using an epigenome-wide search, we found that REST regulates expression of a subset of transcriptionally-responsive genes in response to ischemic insults. New directions include 1) REST-dependent epigenetic remodeling and activation of the Kv7 (KCNQ) family of potassium channels implicated in dendritic excitability in global ischemia; and 2) REST-dependent epigenetic remodeling and silencing of networks of microRNAs in postischemic neurons. This is significant in that neuron-specific microRNAs are thought to play a critical role in silencing networks of non-neuronal genes in neurons. We expect this research to have a major impact on amelioration of the neuronal death and impaired cognition associated with ischemic stroke. To perform this research, we use molecular genetics, electrophysiology and delivery of engineered cDNA and shRNA constructs directly into the brains of living animals via the lentivirus expression system and behavior. We also use transgenic mice in which REST can be conditionally knocked out in any cell type.
In another direction, we are studying epigenetic mechanisms that regulate synaptic proteins during postnatal brain development. We discovered that REST is activated in neurons in the critical period, a time of heightened plasticity, during postnatal development and drives the developmental switch in NMDA receptors by orchestrating epigenetic modifications at the promoters of genes encoding the immature NMDA receptor subunit GluN2B. We found that REST is causally related to the developmental switch. Adverse experience early in life in the form of maternal deprivation disrupts activation of REST and acquisition of the mature NMDA receptor phenotype. These findings document a role for REST-dependent epigenetic remodeling in experience-dependent fine-tuning of genes involved in synaptic plasticity under physiological conditions. We recently found that REST abundance in neurons is controlled at the level of protein stability via ubiquitin-based proteasomal degradation and identified casein kinase 1 (CK1) as an upstream signal that negatively regulates levels of REST in differentiated neurons under physiological and pathological conditions. New directions include a role for polycomb proteins in the developmental switch in NMDA receptors, a role for microRNA-101 in activation of polycomb proteins and a role for DNA methylation in ‘locking in’ expression or silencing of REST targets. Findings from this research are expected to enhance our understanding of NMDAR function as it pertains to memory, synaptic stabilization, brain development and cognitive information flow and how adverse experience in the form of maternal deprivation acts via epigenetic mechanisms to impair normal brain development.
In a third direction, we are studying mouse models of autism including Fragile X syndrome. A major focus has been overactivated mTOR signaling in mouse models of autism. Fragile X Syndrome is the most common inherited cause of intellectual disabilities and a leading cause of autism. The neuroanatomical hallmark of Fragile X is an overabundance of thin, filopodial-like dendritic spines, a factor thought to underlie impaired cognition. Whereas aberrant spine morphology and density in Fragile X has been an area of intense research for nearly two decades, the cause of this defect are, as yet, unclear. We recently found that the actin depolymerizing factor cofilin, a downstream target of the Rho GTPase Rac1 and major determinant of dendritic spine structure, is dysregulated in Fragile X and is causally related to spine abnormalities. Cofilin phosphorylation was elevated (indicative of inactivation) in the somatosensory cortex of young Fragile X mice, which model this disorder in humans. Consistent with this, the filamentous to globular (F/G) actin ratio, a functional readout of cofilin inactivation, was elevated. Phosphorylation of LimK1 and the phosphatase Slingshot1 were also elevated. This is significant in that Slingshot1 and LimK1 are downstream targets of Rac1/PAK1 and upstream regulators of cofilin. Inhibition of PAK1 with a small molecule inhibitor rescues cofilin signaling in Fragile X mice, consistent with a causal relation between PAK1 and cofilin signaling. We found that viral delivery of a constitutively active cofilin mutant (cofilin-S3A) into the somatosensory cortex of Fmr1 KO mice rescued the immature dendritic spine phenotype and elevated spine density. These findings demonstrate a causal relation between elevated Rac1/cofilin signaling and spine defects in Fragile X and uncover a previously unappreciated role for unchecked cofilin activity in the aberrant spine morphology and spine density associated with this serious human condition. New directions include the impact of dysregulated cofilin signaling on contextual learning and cognition and a role for mTOR complex 2 (mTORC2) in regulation of cofilin, spine morphogenesis and cognition.
A hallmark feature of the Fragile X mouse, which models this disorder in humans, is exaggerated, protein synthesis-independent mGluR long term depression. AMPA receptors play a critical role in fast excitatory synaptic transmission and many forms of synaptic plasticity including mGluR-LTD. Whereas dysregulation of AMPA receptor trafficking is well-characterized, little is known regarding AMPA receptor mRNA distribution or transcription in Fragile X. We recently used a novel technique involving single molecule detection to document the topographic distribution of individual endogenous AMPA receptor mRNAs in dendrites and present at transcription sites of hippocampal neurons and show that mRNA encoding the AMPA receptor subunit GluA2 (but not GluA1) is elevated in neurons of Fragile X mice. We further show that expression of CPEB3, an RNA binding protein implicated in the formation of memories, is elevated and causally related to the increase in GluA2 mRNA in dendrites and at transcription sites in Fragile X neurons. Whereas overexpression of CPEB3 phenocopies in wild-type neurons the elevated GluA2 mRNA observed at transcription sites in Fragile X neurons, acute RNAi-mediated knockdown of CPEB3 restores the elevated GluA2 mRNA observed in Fragile X neurons to near wild-type levels. Importantly, we show that CPEB3 associates with and facilitates binding of the transcription factor STAT5b at the promoter of gria2 (gene encoding GluA2), and drives active transcription of GluA2, the AMPA receptor ion-gate keeper. Association of CPEB3 with STAT5b is enriched at the gria2 promoter and is causally related to the increase in GluA2 transcription in Fragile X neurons. This study identifies CPEB3 as a novel target for therapeutic intervention in Fragile X syndrome. Moreover, it reveals a novel mechanism by which GluA2 mRNA localization and transcription are regulated in Fragile X neurons, findings with far-reaching implications for impaired learning and memory in Fragile X syndrome. New directions include the impact of CPEB3 on the functional properties of AMPA receptors and hippocampal-based behaviors.
Positions for graduate students and post-doctoral fellows are available in all 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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