PhD Genetics and Molecular Biology 1998
Ex. PSL 1000/2000
Detailed Description: Our laboratory has a long-standing interest in the development of new therapies for psychiatric disease. Our approach to this problem has been to use mouse models to understand how susceptibility genes alter brain function, and to test genetic and pharmacological interventions for their ability to normalize brain function. As a graduate student I developed a line of mice that has reduced levels of NMDA receptors. For the past 15 years, these mice have afforded many laboratories, including my own, the ability to study the consequences of NMDA receptor dysfunction in vivo. We generated the first genetic model to test the glutamate hypothesis of schizophrenia and to search for new therapies.
Currently, we are testing several hypotheses about the neural substrates of psychosis. First, we believe that a core feature of schizophrenia is the reduction in glutamatergic synapses and dendritic spine density. Based on this hypothesis, we are studying the molecular mechanisms by which reduced NMDA receptor function ultimately leads to a loss of spines. We are now testing whether manipulations of RhoGTPase signaling will improve the behavioral impairments of NMDA receptor knockdown mice through changes in spine density.
We also hypothesize that psychosis results from a loss of dynamic range in dopamine signaling. We are testing this hypothesis with the use of pharmacologic and genetic interventions that modulate dopamine neuron firing patterns and signaling. This work will provide fundamental insights into the way that dopamine neuron dysregulation translates into psychosis. Our approach is to use Cre/lox technologies to achieve dopamine-selective rescue of NMDA receptor levels and examine which behavioral abnormalities are restored as a consequence of intrinsic dopamine neuron activity.
Third, we are studying the developmental consequences of NMDA receptor dysfunction. We are working to determine how much of the pathology that results from NMDA receptor dysfunction is due to miswiring of neural circuits, and whether the adult brain has sufficient plasticity to properly rewire. Our studies use a tamoxifen-inducible Cre system to restore NMDA receptor levels at different developmental stages. We have discovered that the plasticity of schizophrenia-relevant behaviors may be more dependent on brain region and neural circuit than on developmental age.
Neurons, Adenovirus, Behavioral tests, Elisa, Gene expression analysis, Immunohistochemistry, Immunocytochemistry, qRT-PCR, RT-PCR, Signal transduction characterization, Western blot
Analytical balances, benchtop centrifuge, blotting apparatus, culture hood, culture incubators, cryostat , departmental beta and gamma counters, dissecting microscope, fluorescence microscope, fresh tissue sectioning systems, gel apparatus, low- and high-speed centrifuge, low and ultralow freezers, real-time/thermocycler, vibratome, water baths
Outside the Department of Physiology:
Richard Bazinet, Nutritional Sciences, University of Toronto
Stephanie Borgland, Hotchkiss Brain Institute, University of Calgary
Carrie Jones, Vanderbilt University, USA
Craig Lindsley, Vanderbilt University, USA
Sara Jones, Physiology and Pharmacology, Wake Forest University, USA
Liza Barki-Harrington, Haifa University, Israel
Committee Member or Officer of national/international scientific organizations
GRANT COMMITTEES (CURRENTLY SERVING)
Committee: BSA Panel: Operating Grant & Foundation Scheme
Ruddy RM, Milenkovic M, Chen YX, Ramsey AJ. (2015) Differential effects of NMDA receptor antagonists on spine density. Synapse 69(1):52-6.
Bermejo MK, Milenkovic M, Salahpour A, Ramsey AJ. (2014) Preparation of protein from the synaptic plasma membrane and postsynaptic density by sucrose density gradient centrifugation. Journal of Visualized Experiments (91):e51896.
Milenkovic M, Mielnik CA, Ramsey AJ. (2014) NMDA receptor deficient mice display sexual dimorphism in onset and severity of behavioural abnormalities. Genes, Brain, Behavior 13(8):850-62.
Mielnik CA, Horsfall W, Ramsey AJ. (2014) Diazepam improves aspects of social withdrawal and neuron activation in NMDA receptor deficient mice. Genes, Brain, Behavior 13(7):592-602.
Ferris MJ, Milenkovic M, Liu S, Mielnik CA, Beerepoot P, John CE, España RA, Sotnikova TD, Gainetdinov RR, Borgland SL, Jones SR, Ramsey AJ. (2014) Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling. European Journal of Neuroscience 40(1):2255-63.
Ramsey AJ, Medvedev IO, Urs N, Bermejo KM, Sotnikova TD, Beaulieu JM, Gainetdinov RR, Salahpour A. (2013) D1 dopamine receptor coupling to PLC-beta regulates forward locomotion in mice. Journal of Neuroscience 33(46):18125-33.
Ramsey AJ, Milenkovic M, Oliveira AF, Escobedo-Lozoya Y, Seshadri S, Salahpour A, Sawa A, Yasuda R, Caron MG. (2011) Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner. Proc Natl Acad Sci U S A. 108(14):5795-800.
Ramsey AJ, Laakso A, Cyr M, Sotnikova TD, Salahpour A, Medvedev IO, Dykstra LA, Gainetdinov RR, Caron MG (2008) Genetic NMDA receptor deficiency disrupts acute and chronic effects of cocaine but not amphetamine. Neuropsychopharmacology 33(11):2701-14.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98(4):427-36.
Mielnik CM and Ramsey AJ (2015) Drugs that target the glutamate synapse: implications for the glutamate hypothesis of schizophrenia. In Drug Discovery for Schizophrenia: Editor T Lipina. Royal Society of Chemistry Press.
Ramsey AJ (2009) NR1 knockdown mice as a representative model of the glutamate hypothesis of schizophrenia. Progress in Brain Research 179:51-58.