Karen Stevens, PhD
The research uses rodent models of a sensory inhibition deficit commonly observed in schizophrenia to investigate underling mechanisms and to develop new drug therapies. Both mouse and rat models are employed. Deficient sensory inhibition is the inability to adequately “filter” incoming sensory stimuli to keep the brain from responding to repetitive information. A failure of this inhibitory system can lead to sensory overload or “flooding”. This flooding interferes with attention, learning and memory and may contribute to psychosis. Our primary research uses a mouse model which has both phenotypic and genotypic similarities to schizophrenia. Specifically, the strain of inbred mouse (DBA/2) spontaneous shows deficient sensory inhibition using a paradigm in which 2 identical auditory stimuli are delivered 0.5 sec apart and recording the electrophysiological response to both stimuli. Normal sensory inhibition shows a reduced response to the second stimulus. A deficiency, such as these mice and schizophrenia patients have, shows a similar magnitude response to both stimuli. Additionally, schizophrenia patients and DBA/2 mice both have reduced numbers of a specific nicotinic receptor subtype, the alpha 7, on hippocampal interneurons, and both show polymorphisms in the gene coding for this receptor. Current work centers on a developmental intervention which can permanently improve sensory inhibition in the mouse model as well as development of new drugs to ameliorate the deficit. In addition, a chronic recording model using awake and behaving rats is being used to further investigate the mechanisms of deficient sensory inhibition. These studies use intracerebroventricular injections of antisense oligonucleotides specific for the mRNA of selected neurotransmitter receptors to alter the numbers of the receptors in order to study the role of these receptors in normal and deficient sensory inhibition.
Recent Publications:1. Stevens, K.E., Fuller, L.L. and Rose, G.M.; Dopaminergic and noradrenergic modulation of amphetamine-induced changes in auditory gating potentials, Brain Res., 555: 91-98, 1991.2. Stevens, K.E., Freedman, R., Collins, A.C., Hall, M., Leonard, S., Marks, M.J., and Rose, G.M.; Genetic correlation of hippocampal auditory evoked response and alpha-bungarotoxin binding in inbred mouse strains. Neuropsychopharmacol., 15: 152-162, 1996.
3. Adler, L.E., Olincy, A., Waldo, M., Harris, J., Griffith, J., Stevens, K.E., Flach, K., Nagamoto, H., Bickford, P., Myles-Worsley, M., Coon, H., Byerley, W., Leonard, S. and Freedman, R., Schizophrenia, sensory gating, and nicotinic receptors, Schizophrenia Bull. 24:189-202, 1998.
4. Stevens, K.E., Kem, W.R., Mahnir, V. and Freedman, R.; Selective alpha7 nicotinic agonists normalize inhibition of auditory response in DBA mice, Psychopharmacol. 136:320-327, 1998.
5. Hashimoto K., Iyo M., Freedman R and Stevens K.E. Tropisetrom improved deficient inhibitory auditory processing in DBA/2 mice: Role of alpha7 nicotinic acetylcholine receptors. Psychopharmacol. (in review) 2005.
POSTDOCTORAL RESEARCH TRAINING PROGRAM IN DEVELOPMENTAL PSYCHOBIOLOGYDepartment of Psychiatry
University of Colorado Denver
Denver, CO 80262For additional Information E-mail:
Martin.Reite@UCHSC.edu
If you have any comments or suggestions, feel free to E-mail:
Linda.Greco-Sanders@UCHSC.edu
