Maternal smoking is a risk factor for attention deficit hyperactivity disorder, verbal memory dysfunction and adult antisocial behavior. Since nicotine is a major constituent of tobacco smoke, understanding the consequences of maternal smoking and developmental exposure to tobacco smoke on molecular and behavioral parameters could have important implications for public health. Developmental administration of nicotine in rodents results in biochemical, physiological and behavioral consequences. We have identified hypersensitive passive avoidance learning as a long-lasting behavioral outcome of altering nicotinic acetylcholine receptor (nAChR) function during development. The nAChRs responsible for this effect are expressed in glutamatergic neurons in a corticothalamic circuit. Our pilot studies suggest this change in behavior can be mimicked by maternal administration of nicotine. We have a unique set of tools including knockout mice, conditionally expressing transgenic mice and pharmacological and molecular techniques that have allowed us to begin to identify the anatomical locus and molecular mechanisms underlying this long-lasting behavioral change. The experiments proposed here are designed to address the hypothesis that acetylcholine, acting through high affinity nAChRs, is critical for setting the synaptic properties of corticothalamic glutamatergic neurons in the first two weeks of postnatal development in the mouse. Our Aims are to define the developmental time point(s) when nicotinic receptor activity is necessary for normal passive avoidance learning;to identify molecular changes in development involved in normal passive avoidance behavior;to identify the role of nAChRs in corticothalamic synapse formation;and to use pharmacological techniques and viral vector-mediated expression to reverse changes in passive avoidance behavior. We hypothesize that nicotinic receptors in the corticothalamic circuit are critical for normal synaptic maturation. We propose that this mouse model may have implications for the development of psychiatric disorders in subjects exposed to nicotine in utero.