Description) There is an extensive literature showing that fetal nicotine exposure, due to maternal smoking, alters embryonic brain development and results in a variety of pathological effects in the neonate that fall under the heading of the """"""""fetal nicotine syndrome"""""""". Although the mechanisms involved are not well understood, they are thought to be mediated in part by nicotinic acetylcholine receptors in the fetal brain. Yet neither the existence of functional nicotinic receptors in early fetal mammalian brain nor their role in development are well established. The investigators have obtained preliminary evidence that functional nicotinic receptors are expressed on mouse cerebral cortical cells at early embryonic ages when the cortex consists mainly of dividing stem and progenitor cells. Initial results show that nicotinic agonist activation of these receptors evokes characteristic electrophysiological responses and cytosolic Ca++ signals in the E10 cells. These early findings now open up an interesting set of questions concerning the role nicotinic receptors play in early cortical development and how chronic fetal nicotine exposure may alter such development. Before one can address these long term issues, however, it is first necessary to resolve the more focused issues concerning the acquisition, properties, and cellular localization of functional nicotinic receptors in the developing cerebral cortex. Thus, the investigators' specific aims are to answer the following two questions: at what stages of embryonic development do mouse cerebral cortical cells acquire functional nicotinic Ach receptors? And which subtypes of nicotinic receptors are present in the mouse cortex at different stages of development and which neural cells types are they on? Isolated mouse cerebral cortical cells derived from E10, E13, and E18 embryos will be used. Receptor functionality will be assessed by nicotinic agonist-induced Ca++ signaling and patchclamp electrophysiology. Receptor subtypes will be identified by pharmacological and kinetic analysis of functional responses. Immunocytochemistry will also be used to identify receptor subtypes and the different neural cell types they may be on. The results of this project will lay the groundwork for further exploration of the role of nicotinic receptors in normal development and that of nicotine as a neuroteratogen.
| Schneider, A S; Atluri, P; Shen, Q et al. (2002) Functional nicotinic acetylcholine receptor expression on stem and progenitor cells of the early embryonic nervous system. Ann N Y Acad Sci 971:135-8 |
| Atluri, P; Fleck, M W; Shen, Q et al. (2001) Functional nicotinic acetylcholine receptor expression in stem and progenitor cells of the early embryonic mouse cerebral cortex. Dev Biol 240:143-56 |
