The heaviest smoking populations in the US include patients with schizophrenia (SZ). Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognemonic deficits of sensory-gating. Recent studies demonstrate a higher degree of dependence on nicotine in SZ vs. control populations. Genetic variations in the alpha 7 nicotinic acetylcholine receptor (a7*-nAChR) are linked with the sensory gating deficits associated with SZ. Likewise, genetic variants of Neuregulin 1 (Nrg1), a key regulator of (a7*-nAChRs), have recently been associated with heritab e forms of SZ. These observations prompt our proposal of convergent effects on Nrg1 and a7*-expression in the co-morbidity of nicotine abuse and susceptibility to neuropsychiatric disorders such as SZ. CEBRA stage 1 funding is sought to initiate in vivo electrophysiology and behavioral studies in single and compound genetically-modified mice. The genetically altered lines to be examined include the isoform specific: Type Ill-Nrg1 heterozygous mutant (Nrg1) and the a7 nAChR subunit mutant Chrna7(). Proposed studies begin tests of the hypothesized convergence of Nrg1 and a7 regulation as heritable components of susceptibility to nicotine effects, tobacco dependence and facets of SZ phenotypes by comparison of mice prenatal nicotine exposure. Thus, the AIM of this STAGE 1 Application is to initiate tests of whether deficits in Nrg1 (with and without deficits in a7) alter the development, maintenance and/or plasticity of hippocampal-accumbens circuits in vivo. Assessment of genotype dependent changes in synaptic circuits and nicotine-induced excitability in intact systems examine ventral hippocampal-striatal interactions using in vivo intracellular and multi unit recordings. The impact of genetic profile on excitatory-input gating to the ventral striatum and on the effects of nicotine will be assessed in parallel behavioral studies and recordings from adult mice subjected to prenatal and/or acute nicotine exposure.
| Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W et al. (2008) Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons. J Cell Biol 181:511-21 |
| Zhong, Chongbo; Du, Chuang; Hancock, Melissa et al. (2008) Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. J Neurosci 28:9111-6 |
| Chen, Ying-Jiun J; Johnson, Madeleine A; Lieberman, Michael D et al. (2008) Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci 28:6872-83 |
