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Molecular mechanism of neuronal plasticity
The focus of our research is to identify mechanisms of protein synthesis-dependent neuronal plasticity. The approach uses differential cloning techniques to identify mRNAs that are rapidly induced in neurons by synaptic activity. Classical studies established that rapid, de novo protein synthesis is required for long-term memory, and we developed animal models that maximize the induction of candiate genes that are involved in this response. Over the past several years, we have examined the composition and contribution of these genes to neuronal function. Gene products that are linked to protein synthesis dependent plasticity include transcription factors, cytoskeletal proteins, growth factors, metabolic enzymes and proteins involved in signal transduction. The biochemical and cell biological properties of these molecules provide important insights into mechanisms that contribute to neuronal plasticity. Currently, we are focusing on a subset of immediate early genes that function directly at the excitatory synapse; these include Homer, Arc, and Narp. Homer binds and modifies the signaling of group 1 metabotropic glutamate receptors and ion channels that regulated intracellular stores of calcium. Arc functions as a regulatory factor for an endocytosis pathway that selectively traffics AMPA type glutamate receptors and mediates homeostatic scaling of neuronal excitability. Narp functions as an extracellular aggregating factor that binds AMPA receptors and plays a role in excitatory synaptogenesis. Animal models that delete or modify the function of these proteins identify important roles in learning and memory, drug addiction and inflammatory pain. These studies provide insight into how rapid transcriptional events can contribute to synapse-specific plasticity in normal and pathological conditions.
Cho RW, Park JM, Wolff SBE, Xu D, Hopf C, Kim J-A, Reddy RC, Petralia RS, Perin MS, Linden DJ, Worley PF. (2008) mGluR1/5-dependent Long-Term Depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE. Neuron Vol. 57(6), 858-871.
Park S, Park JM, Kim S, Kim J-A, Ryazanov AG, Linden DJ, and Worley PF. (2008) Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD. Neuron Jul 10; 59(1),70-83.
Chowdhury S, Shepherd J, Okuno H, Lyford G, Petralia R, Plath N, Kuhl D, Huganir RL, and Worley PF. (2006) Arc/Arg3.1 Interacts with the Endocytic Machinery to Regulate AMPA Receptor Trafficking. Neuron, Vol. 52(3): 445-459. [PDF]
Shepherd J, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, and Worley PF. (2006) Arc/Arg3.1 Mediates Homeostatic Synaptic Scaling of AMPA Receptors. Neuron, Vol. 52(3): 475-484. [PDF]
Huang G, Zeng W, Kim JY, Yuan JP, Han LH, Muallem S, and Worley PF. (2006) STIML carboxyl-terminus activates native SOC, /crac and TRPC1 channels. Nature Cell Biology, Vol. 8(9): 1003-1010. [PDF]
Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF, Kalivas PW. et al. (2004). Homer Proteins Regulate Sensitivity to Cocaine Neuron, 43(5):401-13.
Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell. 2003 Sep 19;114(6):777-89.