Mechanisms underlying sustained synaptic release of glutamate

Fast communication between neurons in the brain is mediated mainly by amino acid transmitters, such as glutamate, GABA and glycine. These transmitters are stored in small synaptic vesicles which undergo exocytosis at synaptic release sites (active zones) in response to action potentials. Synaptic transmission often occurs at very high rates, thus making high demands on the efficiency of the release machinery.

This thesis explores two mechanisms which are of importance in sustaining transmitter release at glutamatergic synapses. The first concerns the organization of synaptic vesicles at release sites. The major pool of synaptic vesicles is shown to depend on synapsin for its organization, while a small pool located in the vicinity of the presynaptic membrane is independent of synapsin. Disruption of the synapsin-dependent vesicle pool by presynaptic antibody injection in lamprey or gene knockout in mice, was found to impair sustained glutamate release, whereas release at low rates was unaffected.

The second mechanism concerns the supply of neurotransmitter to synaptic vesicles. The synthesis and turnover of transmitter glutamate is shown to be linked to the pattern of release activity. Quantitative immunogold analysis of lamprey and crayfish synapses showed that the axoplasmic matrix and mitochondria in nerve terminals adapted to high levels of activity(tonic synapses) contain a higher glutamate concentration than in those adapted to low levels(phasic synapses). This will ensure a rapid refilling of the synaptic vesicles during periods of sustained release. The concentration of transmitter glutamate in synaptic vesicles was estimated to be more than 60 mM. In addition, the uptake of glutamate analogs into perisynaptic glial processes was found to be more efficient in tonic than in phasic synapses and the level of a major glutamate precursor, glutamine, was also found to be higher in tonic synapses.