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RAYMOND, L.A.

DR. LYNN A. RAYMOND

B.Sc. Chemistry (Rochester)

Ph.D., M.D. (Albert Einstein College of Medicine)

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ROLE OF NMDA RECEPTOR FUNCTION IN HUNTINGTON'S DISEASE

Although it is not known why the GABAergic medium-sized spiny neurons (MSNs) of the striatum are preferentially targeted for degeneration in Huntington's disease (HD), a body of evidence supports a role for excitotoxic cell death mediated by the release of glutamate from cortical afferents and activation of the N-methyl-D-aspartate (NMDAR)-type glutamate receptor. Therefore, we are investigating whether mutant huntingtin (htt) expression can cause increased activity of NMDARs or their downstream effectors of cell death, and how such interactions might explain selective neuronal vulnerability. We have previously reported enhancement of NMDAR-mediated current amplitude and apoptosis in cell lines expressing full-length mutant htt and the NR1A/NR2B but not NR1A/NR2A subtype of NMDARs (Chen et al., 1999; Zeron et al., 2001). Notably, MSNs primarily express the NR1A and NR2B subunits (Landwehrmeyer et al., 1995; Kuppenbender et al., 1999), whereas other forebrain regions express combinations of both NR2A and NR2B with a variety of NR1 splice variants, and the cerebellum and brain stem lack NR2B (Hollmann and Heinemann, 1994). Specific aims of this project include investigating: 1) whether NR1/NR2B-type NMDAR current and calcium influx is increased in striatal neurons from transgenic mice models of HD; 2) whether striatal neurons from HD mice are more sensitive to NMDAR-induced cell death, and the intermediate pathways from NMDAR activation to death; 3) mechanisms of modulation of NMDAR function by mutant htt. This project is a collaboration with Dr. Michael Hayden.

MECHANISMS OF MODULATION OF NMDA RECEPTOR FUNCTION

Fast excitatory synaptic transmission in the brain is mediated largely by activation of 3 subclasses of ionotropic glutamate receptors. The N-methyl-D-aspartate receptor (NMDAR) subclass plays a key role in neuroplasticity, including synaptogenesis during development and activity-dependent modification of synapses in adult brain that may contribute to learning and memory. NMDAR activation also may contribute to cell death associated with neurodegenerative diseases and stroke. NMDARs are heteromeric proteins composed of NR1 with NR2 and/or NR3 subunits. The four NR2 subunits - NR2A, NR2B, NR2C and NR2D - show distinct spatial and temporal expression patterns in the brain, interact differentially with intracellular proteins, and modulate channel properties. Thus, NMDAR subunit composition (i.e., subtype) may contribute importantly to differences among neuronal populations with respect to glutamate-evoked synaptic transmission, plasticity and excitotoxicity. Studies in our lab and others indicate that ions such as Ca²⁺ and Zn²⁺, as well as interactions of NMDARs with intracellular proteins, modulate NMDAR function in a subtype-dependent manner. A major focus of the laboratory is to elucidate further the mechanisms underlying regulation of NMDAR function, in order to increase understanding of the role of NMDAR subtypes, modulatory ions, and protein partners in synaptic plasticity and disease.

Recent work:  Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA (2010) Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 65:178-190.

Increased extrasynaptic NMDAR function revealed in Huntington's mice using the glial glutamate uptake inhibitor TBOA.

Selected References:

• Kaufman AM*, Milnerwood AJ*, Sepers M, Coquinco A, She K, Wang L, Lee H, Craig AM, Cynader M, Raymond LA. Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in co-cultured striatal and cortical neurons. Journal of Neuroscience, in press.

• Fan J, Gladding CM, Wang L, Zhang LYJ, Kaufman A, Milnerwood AJ, Raymond LA.  P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiology of Disease, Dec 14, 2011 [Epub ahead of print] PMID:22198502

• Petkau TL, Neal SJ, Milnerwood A, Mew A, Hill AM, Orban P, Gregg J, Lu G, Feldman HH, Mackenzie IR, Raymond LA, Leavitt BR. (2012) Synaptic dysfunction in progranulin-deficient mice. Neurobiology of Disease, 45:711-722.

• Gladding CM and Raymond LA. (2011) Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Molecular Cellular Neuroscience, 48:308-320.

• Raymond LA, André VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS. (2011) Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience, 198:252-273.

• Tapia L, Milnerwood A, Guo A, Mills F, Yoshida E, Vasuta C, Mackenzie IR, Raymond L, Cynader M, Jia W, Bamji SX. (2011) Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. Journal of Neuroscience, 31:11126-11132.

• Singaraja RR, Huang K, Sanders SS, Milnerwood AJ, Hines R, Lerch JP, Franciosi S, Drisdel RC, Vaid K, Young FB, Doty C, Wan J, Bissada N, Henkelman RM, Green WN, Davis NG, Raymond LA, Hayden MR. (2011) Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Human Molecular Genetics, 20:3899-3909.

• Milnerwood AJ and Raymond LA. (2010) Early synaptic pathophysiology in neurodegeneration:  Insights from Huntington’s disease. Trends in Neuroscience, 33:513-523.

• Fan J, Vasuta OC, Zhang LYJ, Wang L, George A, Raymond LA. (2010) N-Methyl-D-Aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through postsynaptic density 95.  Journal of Neurochemistry, 115:1045-1056.

• Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA (2010) Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 65:178-190. see preview by Levine et al. Neuron 65:145-147, faculty of 1000 selection by H. Bading et al., UBC press release, and ALZ Forum news about this paper.

• Fan J, Cowan CM, Zhang LY, Hayden MR, Raymond LA (2009) Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease. J. Neurosci. 29:10928-10938.

• Graham RK, Pouladi MA, Joshi P, Lu G, Deng Y, Wu NP, Figueroa BE, Metzler M, Andre VM, Slow EJ, Raymond L, Friedlander R, Levine MS, Leavitt BR, Hayden MR (2009) Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease. J. Neurosci. 29:2193-2204.

• Sornarajah L., Vasuta O.C., Zhang L., Sutton C., Li B., El-Husseini A., Raymond L.A. (2008) NMDA receptor desensitization regulated by direct binding to PDZ1-2 domains of PSD-95. J. Neurophysiol. 99(6):3052-3062.

• Cowan C.M., Fan M.M., Fan J., Shehadeh J., Zhang L.Y., Graham R.K., Hayden M.R., Raymond L.A. (2008) Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J. Neurosci. 28(48):12725-35.

• Fan M.M., Zhang H., Hayden M.R., Pelech S.L., Raymond L.A. (2008) Protective up-regulation of CK2 by mutant huntingtin in cells co-expressing NMDA receptors. J. Neurochem. 104(3):790-805.

• Fan M.M., Raymond L.A. (2007) N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol. 81(5-6):272-293.

• Fan M.M., Fernandes H.B., Zhang L.Y., Hayden M.R., Raymond L.A. (2007) Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J. Neurosci. 27(14):3768-3779.

• Milnerwood A.J., Raymond L.A. (2007) Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load. J. Physiol. 15;585(Pt3):817-831.

• Fernandes H.B., Baimbridge K.G., Church J., Hayden M.R., Raymond L.A. (2007) Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington's disease. J. Neurosci. 27(50):13614-13623.

• Cowan C.M., Raymond L.A. (2006) Selective neuronal degeneration in Huntington's disease. Curr. Top. Dev. Biol. 75:25-71.

• Shehadeh, J., Fernandes, H.B., Zeron Mullins, M.M., Graham, R.K., Leavitt, B.R., Hayden, M.R., Raymond, L.A. (2006) Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiology of Disease, 21(2):392-403.

• Yanai, A., Huang, K., Kang, R., Singaraja, R.R., Arstikaitis, P., Gan, L., Orban, P.C., Mullard, A., Cowan, C.M., Raymond, L.A., Drisdel, R.C., Green, W.N., Ravikumar, B., Rubinsztein, D.C., El-Husseini, A., Hayden, M.R. (2006) Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nature Neuroscience 9(6):824-831.

• Graham R.K., Deng Y., Slow E.J., Haigh B., Bissada N., Lu G., Pearson J., Shehadeh J., Bertram L., Murphy Z., Warby S.C., Doty C.N., Roy S., Wellington C.L., Leavitt B.R., Raymond L.A., Nicholson D.W., Hayden M.R. (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125(6):1179-1191.

• Graham, R.K., Slow, E., Deng, Y., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Raymond, L.A., Leavitt, B.R., Hayden, M.R. (2006) Levels of mutant huntingtin influence the phenotype of HD. Neurobiology of Disease, 21(2):444-455.

• Leavitt, B.R., van Raamsdonk, J., Shehadeh, J., Fernandes, H., Wellington, C.L., Raymond, L.A., Hayden, M.R. (2006) Wild-type huntingtin protects neurons from excitotoxicity. Journal of Neurochemistry, 96(4):1121-1129.

• Chen, N., Li, B., Murphy, T.H., and Raymond, L.A. (2004) Site within NMDA receptor pore modulates channel gating. Molecular Pharmacology, 65:157-164.

• Zeron, M.M., Fernandes, H.B., Krebs, C., Shehadeh, J., Wellington, C.L., Leavitt, B.R., Baimbridge, K.G., Hayden, M.R., and Raymond, L.A. (2004) Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington disease. Molecular and Cellular Neuroscience, 25:469-479.

• Li, L., Murphy, T.H., Hayden, M.R., Raymond, L.A. (2004) Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor mediated synaptic currents in a mouse model of Huntington's disease. Journal of Neurophysiology, 92(5):2738-2746.

• Li, B., Otsu, Y., Murphy, T.H., and Raymond, L.A. (2003) Developmental decrease in NMDA receptor desensitizaiton associated with shift to synapse and interaction with PSD-95. Journal of Neuroscience, 23:11244-11254.

• Li, L., Fan, M., Icton, C.D., Chen, N., Leavitt, B.R., Hayden, M.R., Murphy, T.H., Raymond, L.A. (2003) Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease. Neurobiology of Aging, 24:1113-1121.

• Krebs, C., Fernandes, H.B., Sheldon, C., Raymond, L.A., Baimbridge, K.G. (2003) Functional NMDA receptor subtype 2B is expressed in astrocytes after ischemia in vivo and anoxia in vitro. J. Neuroscience, 23:3364-3372.

• Metzler, M., Li, B., Gan, L., Georgiou, J., Gutekunst, C.-A., Torre, E., Devon, R.S., Oh, R., Legendre-Guillemin, V., Rich M., Alvarez, C., Gertsenstein, M., McPherson, P.S., Nagy, A., Roder, J.C., Raymond, L.A., Hayden, M.R. (2003) Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking. EMBO Journal, 22:3254-3266.

• Raymond, L.A. (2003) Excitotoxicity in Huntington disease. Clinical Neuroscience Research, 3:121-128.

• Zeron, M.M., Hansson, O., Chen, N., Wellington, C.L., Leavitt, B.R., Brundin, P., Hayden, M.R., and Raymond, L.A. (2002) Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33:849-860.

• Li, B., Chen, N., Luo, T., Otsu, Y., Murphy, T.H., Raymond, L.A., (2002) Differential regulation of synaptic and extrasynaptic NMDA receptors by calcium and tyrosine phosphorylation. Nature Neuroscience, 5:833-834.

• Zeron MM, Chen N, Moshaver A, Lee AT-C, Wellington CL, Hayden MR, Raymond LA. (2001) Mutant huntingtin enhances excitotoxic cell death. Mol. Cell. Neurosci. 17:41-53.

• Umemiya M, Chen N, Raymond LA, and Murphy TH (2001) A calcium-dependent feedback mechanism participates in shaping single NMDA miniature EPSCs. J. Neurosci. 21:1-9.

• Chen N, Luo T, Wellington C, Metzler M, McCutcheon K, Hayden MR, and Raymond LA (1999) Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J. Neurochem. 72:1890-1898.

• Chen N, Luo T, Raymond LA. (1999) Subtype-dependence of NMDA receptor channel open probability. J. Neurosci. 19:6844-6854.

• Price CJ, Kim P, Raymond LA. (1999) D1 dopamine receptor-induced cyclic AMP-dependent protein kinase phosphorylation and potentiation of striatal glutamate receptors. J. Neurochem. 73:2441-2446.

• Chen N, Moshaver A, and Raymond LA (1997) Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition. Mol. Pharmacol. 51:1015-1023.

• Umemiya M and Raymond LA (1997) Dopaminergic modulation of excitatory postsynaptic currents in rat neostriatal neurons. J. Neurophysiol. 78:1248-1255.

• Raymond LA, Blackstone CD, and Huganir RL (1993) Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. Nature 361:637-641.

• Raymond LA, Blackstone CD, and Huganir RL (1993) Phosphorylation of amino acid neurotransmitter receptors in synaptic plasticity. Trends Neurosci. 16:147-153.