MOUSE MOLECULAR AND NEUROBIOLOGICAL MODELS

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Data generated largely by investigators of this Conte Center application provide compelling evidence that the alpha 7 nicotinic acetylcholine receptor subunit is a potential target for therapeutic intervention in schizophrenia. These data include the observations that the expression of the alpha7 subunit is reduced in the hippocampus of schizophrenics (Project 1), genetic variants in CHRNA7, the gene that encodes the alpha7 subunit, are associated with schizophrenia and auditory sensory gating deficits (Project 3) and auditory gating deficits are common among schizophrenics and the selective alpha7 agonist DMXB-A improves gating deficits (Project 1). In addition, the alpha7 selective agonist choline has been shown to improve auditory gating in human infants when administered perinatally (Project 2). Strikingly similar data have been obtained in mice. For example, we have shown in mice that 1) auditory gating deficits are correlated with reduced alpha7 receptor expression, 2) genetic variability in Chrna7 is linked to reduced expression of alpha7 receptors and auditory gating deficits, 3) the alpha7 receptor selective agonist DMXB-A improves gating deficits and, 4) perinatal choline improves auditory gating in a gating deficient mouse strain. In Project 4 we will take advantage of the similarities between human and mouse with respect to alpha7 receptors and auditory gating to address fundamental biological questions regarding the specific role of alpha7 receptors and Chrna7 in normal and deficient auditory gating. The specific questions that will be addressed in Project 4 are 1) what is the molecular mechanism(s) through which genetic variability in Chrna7 leads to reduced expression of alpha7 recptors and auditory gating deficits 2) what is the neurobiological mechanism by which reduced expression of alpha7 receptors might lead to gating deficits? and 3) what is the mechanism through which perinatal choline improves auditory gating? Project 4 supports the clinical research of Projects 1 and 2. It performs molecular genetics experiments in parallel with Project 3, and it supports the phenotyping of mice in Projects 5 and 6.