423A Burrill Hall
Office: (217) 244-5620
Lab: (217) 300-2360
Fax: (217) 333-1133
Department of Molecular and Integrative Physiology
524 Burrill Hall
407 South Goodwin Avenue,
Urbana, IL 61801
Homeostatic Regulation of Neural Plasticity in Health and Disease
A hyperexcitable brain circuit is a common neurological abnormality observed in patients with various psychiatric and neurodevelopmental disorders, including schizophrenia and bipolar, mood, and autism spectrum disorders. Identifying and understanding the mechanisms that regulate neuronal excitability will likely reveal novel therapeutic targets for these diseases. My laboratory utilizes various approaches including molecular and cell biology, biochemistry, electrophysiology, and mouse genetics to understand the regulation of neuronal excitability at synaptic as well as network level. Two particular areas in which my laboratory studies include:
1) Ubiquitin proteasome system (UPS)-mediated protein degradation in homeostatic neural plasticity
Our recent work identified an ubiquitin E3 ligase, Murine double minute 2 (Mdm2) plays a major role in regulating synapse elimination. Our research currently focuses on the regulation of Mdm2 and its substrate p53 upon neuronal activity stimulation. We aim to understand how Mdm2-p53 signaling contributes to homeostatic control of neuronal excitability. We also investigate whether and how Mdm2-p53 signaling is disrupted in the mouse model of fragile x syndrome (FXS), the Fmr1 KO.
2) Translational control in homeostatic neural plasticity
In neurons, the messenger RNA (mRNA) can be localized to distal compartments (axons or dendrites) and translated into proteins locally. This local translation is thought to provide efficient and spatial regulations for selected genes in response to stimulations. My long-term effort has identified multiple locally translated proteins involved in various neurodevelopmental events. Because an abnormal gene translation is observed in several neurodevelopmental disorders including FXS and tuberous sclerosis complex (TSC), my research aims to understand how the dysregulated protein translation, particularly near dendrites/synapse, contributes to the deficits of homeostatic synaptic and network plasticity in neurodevelopmental disorders.
Jewett KA, Zhu J, and Tsai NP* (2015) The tumor suppressor p53 guides GluA1 homeostasis through Nedd4-2 during chronic elevation of neuronal activity. J Neurochem 135:226-233
Wilkerson JR*, Tsai NP*, Maksimova MA, Wu H, Cabalo NP, Loerwald KW, Dictenberg JB, Gibson JR and Huber KM (2014). A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep 7:1589-1600 (*equal contribution)
Jakkamsetti V, Tsai NP, Gross C, Molinaro G, Collins KA, Nicoletti F, Wang KH, Osten P, Bassell GJ, Gibson JR and Huber KM (2013) Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for mGluR-dependent long-term synaptic depression. Neuron 80:72-79
Tsai NP*, Wilkerson, JR*, Guo, W, Maksimova, MA, DeMartino, GN, Cowan CW and Huber KM (2012) Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151: 1581-1594 (*equal contribution)
Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15: 431-440, S431.
Tsai NP, Lin YL, Tsui YC, Wei LN (2010) Dual action of epidermal growth factor: extracellular signal-stimulated nuclear-cytoplasmic export and coordinated translation of selected messenger RNA. J Cell Biol 188: 325-333.
Tsai NP, Tsui YC, Pintar JE, Loh HH, Wei LN (2010) Kappa opioid receptor contributes to EGF- stimulated neurite extension in development. Proc Natl Acad Sci U S A 107: 3216-3221.
Tsai NP, Lin YL, Wei LN (2009) MicroRNA mir-346 targets the 5'-untranslated region of receptor interacting protein 140 (RIP140) mRNA and up-regulates its protein expression. Biochem J 424: 411-418.
Tsai NP, Tsui YC, Wei LN (2009) Dynein motor contributes to stress granule dynamics in primary neurons. Neuroscience 159: 647-656.
Tsai NP, Ho PC, Wei LN (2008) Regulation of stress granule dynamics by Grb7 and FAK signalling pathway. EMBO J 27: 715-726.
Bi J, Tsai NP, Lu HY, Loh HH, Wei LN (2008) Copb1-facilitated axonal transport and translation of kappa opioid-receptor mRNA. Proc Natl Acad Sci U S A 104: 13810-13815.
Tsai NP, Bi J, Wei LN (2007) The adaptor Grb7 links netrin-1 signaling to regulation of mRNA translation. EMBO J 26: 1522-1531.
Huq MD, Tsai NP, Lin YP, Higgins L, Wei LN (2007) Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation. Nat Chem Biol 3: 161-165
Bi J, Tsai NP, Lin YP, Loh HH, Wei LN (2006) Axonal mRNA transport and localized translational regulation of kappa-opioid receptor in primary neurons of dorsal root ganglia. Proc Natl Acad Sci U S A 103: 19919-19924.
Tsai NP, Bi J, Loh HH, Wei LN (2006) Netrin-1 signaling regulates de novo protein synthesis of kappa opioid receptor by facilitating polysomal partition of its mRNA. J Neurosci 26: 9743-9749.
Tsai NP, Wu YC, Chen JW, Wu CF, Tzeng CM, Syu WJ (2005) Multiple functions of l0036 in the regulation of the pathogenicity island of enterohaemorrhagic Escherichia coli O157:H7. Biochem J 393: 591-599.