The research uses rodent models of a sensory inhibition deficit commonly observed in schizophrenia to investigate underlying 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.
University of Colorado School of Medicine