Our understanding of the mechanisms that underlie synaptic transmission has been built on a foundation of information from the nerve-muscle junction. Studies over the past 40 years have established that calcium influx through voltage-dependent channels in the nerve terminal membrane triggers release of the transmitter acetylcholine. The release event itself and hydrolysis of acetylcholine are fast, limiting the availability of transmitter in the synaptic cleft to ca. l millisecond. As a result, the time course for synaptic transmission is determined almost entirely by the properties of the postsynaptic, muscle membrane. In these ways, the synchonous, rapid signalling required for coordinated movement is insured. Is this the case for all synapses? One might imagine that the physiological function of a synapse dictates its properties, leading to variations in fundamental mechanisms underlying synaptic transmission. In the central nervous system, for example, where virtually all synaptic potentials are subthreshold, speed of synaptic transmission is likely to be less important than integration of multiple presynaptic inputs--a process promoted by prolonged, not brief, postsynaptic potentials. Indeed, a number of studies have shown that synaptic currents in central neurons exhibit a long-lasting component that could result either from high- affinity postsynaptic receptor binding or maintained availability of transmitter in the synaptic cleft. We have begun to dissect the presynaptic contribution to the time course for synaptic transmission in the central nervous system by studying the release event itself, using a rapid biochemical method with subsecond resolution. Our results argue that, in contrast to acetylcholine release from motoneurons, glutamate release from central nerve terminals is prolonged, suggesting that availability of transmitter within the synaptic cleft might play a role in controlling the time course of synaptic transmission. We have also shown that the calcium channels responsible for glutamate release differ from those at the nerve-muscle junction. Preliminary indications are that fundamental differences exist among the release mechanisms for different transmitters within the central nervous system as well. We propose three specific aims to investigate these mechanisms.
Aim 1 will focus on describing the time course and Aim 2 on identifying the calcium channels responsible for glutamate release.
Aim 3 will compare the release properties for glutamate with those for GABA, norepinephrine, and dopamine. Taken together, results from these studies are likely to highlight means by which we can discriminate (and experimentally regulate) release of different transmitters in the central nervous system. In the long term, such information might prove invaluable for therapeutic management of neurological disorders, such as Parkinsonism and schizophrenia--diseases that are associated with malfunctions in specific neurotransmitter systems.
