Joseph A. Bobich
We are studying the workings of nerve endings, the place in the central nervous system where nerve cells communicate with each other, thoughts are integrated, and responses to both external and internal events are initiated. The basic mechanism underlying nerve ending function is called neurotransmitter release. To produce release, synaptic vesicles filled with neurotransmitter molecules cluster at synaptic contacts in nerve endings, and vesicles closest to the presynaptic membrane are “docked” at release sites. Arrival of a stimulus from the nerve cell body permits calcium ions to enter through gated calcium channels concentrated in the surrounding membrane. Within 0.2 ms this permits docked vesicles to fuse with the membrane. Then the neurotransmitter molecules released to the exterior cross the synaptic gap and change the behavior of follower cells.
Synaptosomes (pinched off and resealed nerve endings) can be isolated from brain homogenates and the synaptosomes retain the machinery to release neurotransmitter molecules normally because their release properties are the same as those demonstrated for living nerve endings.
Synaptosome perforation is a new technique for investigating the neurotransmitter release mechanism. Neuroscientists were skeptical that a structure as delicate as a synaptosome could be perforated to yield a stable, homogeneous preparation that would demonstrate nerve ending neuro-transmitter release characteristics, but such a preparation was achieved in the late 1980s. These preparations now are well characterized with respect to basic release parameters. The results clearly demonstrate that the release machinery is not damaged by perforation because release characteristics are very similar to those occurring in vivo. Therefore, perforated synaptosomes are an excellent model system to bypass the nerve ending membrane and directly investigate molecular components of the release mechanism. This is the preparation we use to study neurotransmitter release.
Neurotransmitter release is the most basic mechanism underlying neural function. Evidence demonstrating roles for neuro- transmitter release in learning and memory emphasizes the central position of this process in brain function, and decreasing effectiveness of learning and memory are hallmarks of the aging process in many people. Therefore, understanding neuro-transmitter release is a challenge with tremendous theoretical and practical consequences.