Huntingtonís disease (HD) is an inherited disorder of mood, movement and cognition with most severe loss of striatal, then cortical neurons; it is caused by CAG expansion >35 in exon1 of HTT, encoding huntingtin (Htt) with an elongated polyglutamine. Synaptic changes precede the motor phenotype, and synaptic proteins form interaction hubs with Htt. Thus, therapy to ameliorate functional deficits in neuronal circuitry may prolong quality of life and provide neuroprotection. Although it is not known why the GABAergic medium-sized spiny projection neurons (SPN) of the striatum are preferentially targeted for degeneration in HD, a body of evidence from our lab and others supports a role for striatal neuronal dysfunction mediated by the release of glutamate from cortical afferents and activation of the N-methyl-D-aspartate (NMDAR)-type glutamate receptor on striatal SPN.
Projects feature mechanistic studies of NMDA receptor trafficking and signaling, glutamate release and uptake, as well as synaptic plasticity (homeostatic synaptic scaling, endocannabinoid-mediated plasticity) at cortico- and thalamo-striatal synapses. Experimental approaches include biochemical and immunocytochemical techniques to examine glutamate receptor synaptic/extrasynaptic localization and downstream signaling, as well as physiological studies using patch clamp recording and optogenetic actuators (e.g., channelrhodopsin) and sensors (e.g., iGluSnFR to detect glutamate release and uptake) in neuronal co-culture (cortico-striatal, thalamo-striatal), organotypic slice culture and acute brain slice. A naturalistic, home-cage behavioural task that is fully automated and customized to individual mice is used to assess progression of motor and cognitive deficits.
Increased extrasynaptic NMDAR function revealed in Huntington's mice using the glial glutamate uptake inhibitor TBOA. Adapted from Milnerwood et al., Neuron, 65:145, 2010.
A variety of previous studies have suggested that glutamate release and uptake in the striatum is altered in Huntington disease. We are investigating this question using a powerful approach to image real-time glutamate dynamics in the acute brain slice. (Collaboration with the TH Murphy lab).
50 Pulse Train
MP Parsons and LA Raymond
High frequency stimulation of cortical afferents to striatal projection neurons results in synthesis and release of endocannabinoids from striatal neurons; eCB bind to presynaptic (cortical) CB1 receptors, which signal to reduce subsequent cortical glutamate release. This retrograde signaling from striatal neurons to cortical afferents via eCB produces long-term depression (LTD), and we have recently discovered this LTD is altered in HD mice, potentially contributing to deficits in motor learning and coordinated movement. We are exploring the underlying molecular mechanisms and potential therapies that target these pathways.
MD Sepers and LA Raymond
Buren C , Wang L, Smith-Dijak A, Raymond LA. (2015)Region-specific Pro-survival Signaling and Global Neuronal Protection by Wild-type Huntingtin. Journal of Huntington disease, 3(4):365-76. PMID:25575958x
Beccano-Kelly DA, Volta M, Munsie LN, Paschall SA, Tatarnikov I, Co K, Chou P, Cao LP, Bergeron S, Mitchell E, Han H, Melrose HL, Tapia L, Raymond LA, Farrer MJ, Milnerwood AJ. (2015) LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Human Molecular Genetics, 24(5):1336-49.
Naydenov AV, Sepers MD, Swinney K, Raymond LA, Palmiter R, Stella N. (2014)
Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice.
Neurobiology of Disease
, 71:140-50. PMID: 25134728
, Raymond LA. (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron,
82(2):279-93. PMID: 24742457
, Parsons MP, Southwell AL, Hayden MR, Raymond LA. (2014)
Striatal synaptic dysfunction and hippocampal plasticity deficits in the hu97/18 mouse model of huntington disease.
, 9(4):e94562. PMID: 24728353
, Raymond LA. (2014)Mechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease. Drug Discovery Today, Jul;19(7):990-6. PMID:24603212
, Fan J, Zhang LY, Wang L, Xu J, Li EH, Lombroso PJ, Raymond LA. (2014)
Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128
Huntington's disease mouse model.
Journal of Neurochemistry
, Jul;130(1):145-59. PMID:24588402
, Kang R, Buren C, Dau A, Southwell AL, Doty CN, Sanders SS, Hayden MR, Raymond LA. (2014) Bidirectional control of
postsynaptic density-95 (PSD-95) clustering by huntingtin. Journal of Biological Chemistry, 289:3518-3528. PMID: 24347167
, Gladding CM,Sepers MD, Raymond LA.
(2014) Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice. Neurobiology of Disease
, Parsons MP, Young FB, Singaraja R, Franciosi S, Volta M, Bergeron S, Hayden MR, Raymond LA. Memory and synaptic deficits in Hip14/DHHC17 knockout mice. (2013) Proceedings of the National Academy of Sciences, 110:20296-20301. PMID:24277827
, Sepers MD, Xu J, Zhang LYJ, Milnerwood AJ, Lombroso PJ, Raymond LA. (2012) Calpain and Striatal-Enriched Tyrosine
Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntingtonís disease mouse model. Human Molecular Genetics, 21:3739-52. PMID: 22523092
, Kaufman AM, Sepers M, Gladding CM, Fan J, Coquinco A, Zhang L, Wang L, Qiao JY, Lee H, Cynader M, Raymond LA. (2012) Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington's
disease mice. Neurobiology of Disease, 48:40-51. PMID: 22668780.
, Gladding CM, Wang L, Zhang LYJ, Kaufman AM, Milnerwood AJ, Raymond LA. (2012) P38 MAPK is involved in enhanced NMDA
receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiology of Disease, 45:999-1009.
Kaufman AM , Milnerwood AJ, Sepers M, Coquinco A, She K, Wang L, Lee H, Craig AM, Cynader M, Raymond LA. (2012) Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in co-cultured striatal and cortical neurons. Journal of Neuroscience, 32:3992-4003.
Gladding CM and Raymond LA. (2011) Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function.† Molecular Cellular Neuroscience, 48:308-320.
Raymond LA, Andr√© 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.
CIHR Investigator and MSFHR Senior Scholar
Director of the PhD/MD program at UBC