Faculty: Amy J. Ramsey, PhD
General Research Areas: Animal models of schizophrenia, neuropharmacology, NMDA receptor biology.
Our laboratory is interested in studying schizophrenia using genetic mouse models of the disease with altered levels of neurotransmitter receptors and regulatory proteins. These models are studied at the molecular level, examining changes in gene expression and protein biology, and at the whole animal level, examining changes in behavioral pharmacology.
One of the principal efforts of our laboratory is to understand the physiological consequences of NMDA receptor deficiency using a genetic mouse model that expresses low levels of the receptor throughout the brain. The NMDA receptor is a subtype of glutamate neurotransmitter receptors that regulates the formation and maintenance of synaptic connections between neurons. It plays an important role in the way that neurons wire together and change the strength of synaptic connections with experience. It is also implicated in a number of disease states including schizophrenia, a devastating mental illness.
Our previous work has demonstrated that NMDA receptor deficient mice represent a model of schizophrenia, exhibiting behavioral abnormalities that can be partially reversed with antipsychotic drugs. More recent studies have focused on the biochemical composition of the synapse, and the resulting morphology of the postsynaptic spine. The goal of our efforts is to understand which proteins and signal transduction systems are altered when NMDA receptors are deficient. This knowledge may provide new insights into therapeutic treatments for schizophrenia, which can be experimentally tested in our model systems.
Bermejo MK, Milenkovic M, Salahpour A, Ramsey AJ. Preparation of synaptic plasma membrane and postsynaptic density proteins using a discontinuous sucrose gradient. J Vis Exp. 2014 Sep 3;(91). doi: 10.3791/51896. PMID:25226023
Ruddy RM, Chen Y, Milenkovic M, Ramsey AJ. Differential effects of NMDA receptor antagonism on spine density. Synapse. 2014 Sep 12. doi: 10.1002/syn.21784. [Epub ahead of print] PMID:25220437
Mielnik CA, Horsfall W, Ramsey AJ. Diazepam improves aspects of social behaviour and neuron activation in NMDA receptor-deficient mice. Genes Brain Behav. 2014 Sep;13(7):592-602. doi: 10.1111/gbb.12155. Epub 2014 Aug 29. PMID:25040071
Vecchio LM, Bermejo MK, Beerepoot P, Ramsey AJ, Salahpour A. N-terminal tagging of the dopamine transporter impairs protein expression and trafficking in vivo. Mol Cell Neurosci. 2014 Jul;61:123-32. doi: 10.1016/j.mcn.2014.05.007. Epub 2014 Jun 2. PMID:24886986
Sustained N-methyl-d-as Ferris MJ, Milenkovic M, Liu S, Mielnik CA, Beerepoot P, John CE, España RA, Sotnikova TD, Gainetdinov RR, Borgland SL, Jones SR, Ramsey AJ. partate receptor hypofunction remodels the dopamine system and impairs phasic signaling. Eur J Neurosci. 2014 Jul;40(1):2255-63. doi: 10.1111/ejn.12594. Epub 2014 Apr 23. PMID:24754704
Medvedev IO, Ramsey AJ, Masoud ST, Bermejo MK, Urs N, Sotnikova TD, Beaulieu JM, Gainetdinov RR, Salahpour A. D1 dopamine receptor coupling to PLCβ regulates forward locomotion in mice. J Neurosci. 2013 Nov 13;33(46):18125-33. doi: 10.1523/JNEUROSCI.2382-13.2013. PMID:24227722
Gregory KJ, Herman EJ, Ramsey AJ, Hammond AS, Byun NE, Stauffer SR, Manka JT, Jadhav S, Bridges TM, Weaver CD, Niswender CM, Steckler T, Drinkenburg WH, Ahnaou A, Lavreysen H, Macdonald GJ, Bartolomé JM, Mackie C, Hrupka BJ, Caron MG, Daigle TL, Lindsley CW, Conn PJ, Jones CK. N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. J Pharmacol Exp Ther. 2013 Nov;347(2):438-57. doi: 10.1124/jpet.113.206623. Epub 2013 Aug 21. PMID:23965381
Siesser WB, Sachs BD, Ramsey AJ, Sotnikova TD, Beaulieu JM, Zhang X, Caron MG, Gainetdinov RR. Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chem Neurosci. 2013 Jan 16;4(1):84-8. doi: 10.1021/cn300127h. Epub 2012 Oct 1. PMID:23336047
Jocoy EL, André VM, Cummings DM, Rao SP, Wu N, Ramsey AJ, Caron MG, Cepeda C, Levine MS. Dissecting the contribution of individual receptor subunits to the enhancement of N-methyl-d-aspartate currents by dopamine D1 receptor activation in striatum. Front Syst Neurosci. 2011 May 11;5:28. doi: 10.3389/fnsys.2011.00028. eCollection 2011. PMID:21617735
Ramsey AJ, Milenkovic M, Oliveira AF, Escobedo-Lozoya Y, Seshadri S, Salahpour A, Sawa A, Yasuda R, Caron MG. Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner. Proc Natl Acad Sci USA. 2011 Apr 5;108(14):5795-800. doi: 10.1073/pnas.1012621108. Epub 2011 Mar 21. PMID:21436042
Department of Pharmacology and Toxicology
Room 4302, Medical Sciences Building
1 King's College Circle