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Séminaire - Suzanne ZukinREST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors

Abstract :

Albert Einstein College of Medicine of Yeshiva University: Suzanne Zukin


  
NMDA receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions. A hallmark feature of NMDARs is an early postnatal developmental switch in NMDAR subunit composition from primarily GluN2B- to primarily GluN2A-containing receptors. This is significant in that GluN2B expression can restrict synaptic incorporation of AMPA receptors, reduce the threshold for and enhance the magnitude of long-term potentiation, and promote hippocampus-dependent learning, plas¬ticity-induced spine growth and dendritic patterning critical to information processing. Although the switch in phenotype has been an area of intense interest for nearly two decades, the mechanisms that trigger it and the link between experience and the switch are unclear.

We recently discovered a novel role for the transcriptional repressor REST in the developmental switch in synaptic NMDARs. We demonstrated that REST is activated at a critical window of time and acts via epigenetic remodeling to repress Grin2b expression and alter NMDAR properties at rat hippocampal synapses. Acute knockdown of REST in vivo prevents the decline in GluN2B and developmental switch in NMDARs, indicating a causal role for REST in the developmental switch. Adverse experience early in life in the form of maternal deprivation disrupts activation of REST and acquisition of the mature NMDAR phenotype.
These findings document a role for REST in the developmental switch in synaptic NMDARs, but do not address the mechanism by which REST is activated in differentiated neurons under physiological conditions.
We further show that REST is controlled at the level of protein stability via β-TrCP-dependent ubiquitin-based proteasomal degradation and identify casein kinase 1 (CK1) as an upstream signal that negatively regulates REST cellular abundance in differentiated neurons under physiological conditions. Thus, REST-dependent epigenetic remodeling is essential for experience-dependent fine-tuning of genes involved in synaptic activity and plasticity.
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 and how adverse experience in the form of maternal deprivation acts via epigenetic remodeling to impair normal brain development.

Selected publications

Kaneko N, Hwang JY, Gertner M, Pontarelli F, Zukin RS (2014). Casein Kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death. J Neurosci 23:6030-9. PMID: 24760862

Murphy J, Stein IS, Lau GC, Peixoto R, Kaneko N, Aromolaran K, Saulnier J, Sabatini BL, Hell JW, Zukin RS (2014). Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. J Neurosci 34:869-879. PMID:24431445

Hwang JY, Kaneko N, Noh KM, Pontarelli F, Zukin RS (2014) The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J Mol Biol 426:3454-66. PMID:25108103

Takeuchi K, Gertner MJ, Zhou J, Parada LF, Bennett, MVL, Zukin RS (2013) Dysregulation of synaptic plasticity precedes morphological defects in a Pten conditional knockout mouse model of autism. Proc Natl Acad Sci USA 110:4738-43. PMID:23487788

Udagawa T, Swanger SA, Takeuchi K, Kim JH, Nalavadi V, Shin J, Lorenz LJ, and Zukin RS, Bassell GJ, Richter JD (2012). Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Mol Cell 47:253-66. PMID:22727665

Rodenas-Ruano A, Chávez AE, Cossio MJ, Castillo PE, Zukin RS (2012). REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci 15:1382-90. PMID: 22960932

Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (2012). 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. PMID: 22371606

Nolt MJ, Lin Y, Hruska M, Murphy J, Sheffler-Colins SI, Kayser MS, Passer J, Bennett MVL, Zukin RS, Dalva M (2011). EphB controls NMDAR function and synaptic targeting in a subunit-specific manner. J Neurosci 31:5353-64. PMID: 21471370

Philpot BD, Zukin RS (2010). Synapse-Specific Metaplasticity: To Be Silenced Is Not to Silence 2B. Neuron 66:814-816. PMID: 20620866

Scientific focus :

There are four major lines of ongoing research in the Zukin lab. First, we are studying 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.   read more..