NFAT-Dependent Transcription Within the Nervous System: A Critical Mediator of Neurotrophin-Induced Plasticity
Associate Director, Biogen
Principal Scientist, Biogen
Senior Principle Scientist, Centers for Therapeutic Innovation, Pfizer
Undergraduate Institution and Major/Degree:
Macalester College, BA, Biology, Neuroscience, 2000
- Paul G. Mermelstein, Ph.D.
- Virginia S. Seybold, Ph.D.
Gene expression activated by the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) underlies such diverse processes as the refinement of neuronal connections during development, to learning and memory within the adult brain, to hyperalgesia following tissue injury and inflammation . To date, however, the mechanisms by which these neurotrophins induce gene expression are not fully understood. Recently, members of the NFATc family of transcription factors have also been implicated in shaping long-term changes in cellular functioning. Intriguingly, neurotrophin signaling appears ideally suited to activate NFATc transcription factors. As such, the experiments of my thesis project are designed to investigate the role of NFAT-dependent transcription in the neurotrophin-mediated gene expression required to establish enduring changes in synaptic neurotransmission. These experiments are organized to address the following three specific aims:
- To determine whether NFAT-dependent transcription underlies BDNF-mediated activity-dependent synaptic plasticity within hippocampal neurons.
- To determine whether NFAT-dependent transcription underlies neurotrophin-mediated activity-dependent synaptic plasticity within DRG and spinal neurons.
- To determine whether neurotrophin-induced NFAT-dependent transcription underlies the development of hyperalgesia .
The proposed research will serve to further the understanding of:(1) the mechanisms by which neurotrophin signaling elicits lasting changes in cellular functioning, (2) the regulation of NFAT-dependent transcription within the nervous system, and (3) the mechanism underlying the establishment of hyperalgesia, with the ultimate goal of identifying novel therapeutic approaches, by examining the role of NFATc transcription factors in neurotrophin-mediated gene expression in vitro and in a model of persistent pain in vivo.
- Virginia Seybold
- Don Simone
- Paul Mermelstein
Courses Taken Beyond the Core Courses:
- GCD 8121 Adv Mol Genetics
- NSC 8221 Neurobiol Pain
- NSC 5462 Neurosci Drug Abuse
- NSC 8222 Cent Reg Auto Funct
Graduate Level Minor:
- Supporting Program
Conferences Attended and Presentations:
- Society for Neuroscience annual meeting - (1999 - 2004)
- Pain Interest Group Meeting (2000, 2003, 2005)
- Glenn Giesler (chair)
- Paul Mermelstein
- Virginia Seybold
- Stan Thayer
- Wheeler DG*, Groth RD*, Ma H*, Barrett CF, Owen SF, Safa P, Tsien RW. Ca(V)1 and Ca(V)2 channels engage distinct modes of Ca(2+) signaling to control CREB-dependent gene expression. Cell. 2012;149(5):1112-24. *Equal Contribution.
- Ma H, Groth RD, Wheeler DG, Barrett CF, Tsien RW. Excitation-transcription coupling in sympathetic neurons and the molecular mechanism of its initiation. Neurosci Res. 2011;70:2-8.
- Groth RD, Lindskog M, Thiagarajan TC, Li L, Tsien RW. Beta Ca2+/CaM-dependent kinase type II triggers upregulation of GluA1 to coordinate adaptation to synaptic inactivity in hippocampal neurons. Proc Natl Acad Sci U S A. 12011;08(2):828-33.
- Lindskog M, Li L, Groth RD, Poburko D, Thiagarajan TC, Han X, Tsien RW. Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivity. Proc Natl Acad Sci U S A. 12010;107(50)21806-811.
- Wheeler DG, Barrett CF, Groth RD, Safa P, Tsien RW. CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling. J Cell Biol. 2008;183:849-863.
- Groth RD, Tsien RW. A role for retinoic acid in homeostatic plasticity. Neuron. 2008;60(2):192-4.
- Groth RD*, Weick JP*, Bradley KC, Luoma JI, Aravamudan B, Klug JR, Thomas MJ, Mermelstein PG. (2008) D1 dopamine receptor activation of NFAT-mediated striatal gene expression. Eur J Neurosci. 2008;27:31-42. *Equal contribution.
- Groth RD, Mermelstein PG. NFAT-Dependent Gene Expression in the Nervous System: A Critical Mediator of Neurotrophin-Induced Plasticity. In: Dudek S (Ed) Transcriptional Regulation by Neuronal Activity. 2007; pp.188-209. New York, Springer.
- Groth RD, Coicou LG, Mermelstein PG, Seybold VS. Neurotrophin activation of NFAT-dependent transcription contributes to the regulation of pro-nociceptive genes. J Neurochem. 2007;102(4):1162-74.
- Seybold VS, Coicou LG, Groth RD, Mermelstein PG. Substance P initiates NFAT-dependent gene expression in spinal neurons. J Neurochem. 2006;97(2):397-407.
- Bradley KC, Groth RD, Mermelstein PG. Immunolocalization of NFATc4 in the adult mouse brain. J Neurosci Res. 2005;82:762-770.
- Boulware MI, Weick JP, Becklund BR, Kuo SP, Groth RD, Mermelstein PG. Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci. 2005;25(20):5066-78.
- Groth RD, Dunbar RL, Mermelstein PG. Calcineurin regulation of neuronal plasticity. Biochem Biophys Res Commun. 2003;311(4):1159-71.
- Groth RD, Mermelstein PG. Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci. 2003;23(22):8125-8134.
- Weick JP, Groth RD, Isaksen AL, Mermelstein PG. Interactions with PDZ proteins are required for L-type calcium channels to activate cAMP response element-binding protein-dependent gene expression. J Neurosci. 2003;23(8):3446-56.
- Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG. Calcitonin gene-related peptide regulates expression of neurokinin1 receptors by rat spinal neurons. J Neurosci. 2003;23:1816-1824.
Awards and Honors:
- (see CV)
- Society for Neuroscience
- Littleton, Colorado