The main objective of this proposal is to study prenatal synaptogenesis in the cortex of human embryos and fetuses. Formation of synapses represents a major event in the cellular differentiation of the brain and it is of the utmost importance for the subsequent development of the normal functional capacity of brain. It is generally accepted that a critical mass of synapses is necessary for the emergence of any particular cortical function and that changes in synaptic density are correlated with changes in cortical function. Furthermore, defects in fine morphological and chemical differentiation of cortical neurons during synaptogenesis may affect mental health and behavior. However, despite its importance, very little quantitative data about synaptic density in human development is available. I have chosen to focus on the Intrauterine phases of human development and to provide necessary quantitative data about early synaptic contacts which are important initial steps in the developmental cascade that results in normal cortical structure and function. To establish baseline data about human prenatal synaptogenesis three specific aims are proposed: l) to determine the synaptic density and laminar distribution of particular synaptic types (asymmetrical, symmetrical, on spines, on dendritic shafts), 2) to characterize cortical synapses by the transmitter they use, and 3) to study possible synaptic active areas using synapsin I, a molecule related to synaptogenesis. Already existing fetal cortical tissue embedded for electron microscopy will be qualitatively and quantitatively analyze"d. Additional fetal cortical tissue will be obtained and labeled with antibodies to dopamine (DA), tyrosine hydroxylase (TH), gama-aminobutyric acid (GABA), glutamate (Glu) and acetylcholine (ACh) for immuno- electron microscopy, while immunohistochemistry for synapsin I will he applied to observe development of synapses in larger blocks of human embryonic and fetal brains. We believe that this, presently missing, knowledge about synaptogenesis in human, will help us to better understand the formation of normal cortical circuitry, as well as genetic and congenital defects of the CNS.