Our earlier work showed the hatchetfish giant synapse to be uniquely valuable for study of central synaptic transmission. Both pre-and postsynaptic elements can be independently penetrated by microelectrodes close to the synapse, quantal PSPs can be recorded, and graded release of quanta can be evoked. Some of the synapses can be localized under visual control to within 50 microns. The presynaptic vesicles are depleted by a short period of rapid stimulation and PSPs are greatly reduced in amplitude, yet transmission continues without failures. These data are interpreted as resulting from release of the contents of partially filled vesicles. We plan to analyze the processes of release, fatigue and recovery, both physiologically and morphologically. We will determine the time course of vesicle filling by analysis of quantal size during recovery from a depleting tetanus. We are voltage clamping the giant fiber and will analyze the effects of potential on the time course of the synaptic current. Because single quanta can be recorded, Ca ion injection presynaptically close to a synapse should give readily detectable transmitter release. Actions and interactions of divalent cations will be studied. Extra-cellular application or intracellular injection of agents such as hemicholinum and choline should allow analysis of packaging and release of transmitter. Voltage clamping postsynaptically defines the PSP reversal potential and reveals voltage dependence of synaptic conductance changes. Habituation of the Mauthner cell mediated by descending pathways. We will localize the sources of the inhibitory fibers and determine if habituation also occurs by inhibition of the Mauthner cell itself.