Mechanisms of Synaptic Transmission and Plasticity
The Process of Synaptic Transmission
The action potential signal arrives at the axon terminal (the bouton). The local depolarization causes Ca channels to open. (Is this channel voltage, chemically, or mechanically gated? Voltage). Ca enters the presynaptic cell because its concentration is greater outside the cell than inside. The Ca, by binding with calmodulin, causes vesicles filled with neurotransmitter to migrate towards the presynaptic membrane.
Neurotransmitter Release and Exocytosis
The vesicle merges with the presynaptic membrane. The presynaptic membrane and vesicle now form a continuous membrane, so that the neurotransmitter is released into the synaptic cleft. This process is called exocytosis. The neurotransmitter diffuses through the synaptic cleft and binds with receptor channel membranes that are located in both presynaptic and post-synaptic membranes. (Are these channels voltage, chemically, or mechanically gated? Chemical). The time period from neurotransmitter release to receptor channel binding is less than a millionth of a second.
Synaptic Efficacy and Plasticity
The efficacy of transmission at a synapse is not fixed, but can vary as a consequence of patterns of ongoing activity. Short trains of presynaptic action potentials can produce either facilitation of transmitter release from the presynaptic terminal that persists for several hundred milliseconds or depression of the release lasting for seconds, or a combination of both.
Short-Term and Long-Term Changes
More prolonged trains of presynaptic action potentials produce post-tetanic potentiation, an increase in transmitter release that can last for several minutes. An intermediate phase of enhancement, classified as augmentation, decays with a time course similar to that of synaptic depression. These changes in synaptic efficacy are closely linked to the accumulation of calcium in the presynaptic cytoplasm during activity and subsequent extrusion. At many synapses, repetitive activity can produce not only short-term changes but also changes in efficacy that can last for days: LTP and LTD.
- LTP (Long-Term Potentiation) is mediated by an increase in Ca in the post-synaptic cell that sets in motion a series of second messenger systems that recruit additional receptors into the post-synaptic membrane and, in addition, increase receptor sensitivity.
- LTD (Long-Term Depression) appears to be associated with smaller increases in post-synaptic Ca concentrations and is accompanied by a reduction in the number and sensitivity of post-synaptic receptors.
The Role of Cyclic AMP in Cellular Signaling
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a multitude of cellular responses. Cyclic AMP formation usually depends upon the activation of G-protein-coupled receptors (GPCRs) that use heterotrimeric G proteins to activate the amplifier adenylyl cyclase (AC), which is a large family of isoforms that differ considerably in both their cellular distribution and the way they are activated.
There are a number of cyclic AMP signaling effectors, such as:
- Protein kinase A (PKA)
- The exchange proteins activated by cyclic AMP (EPACs) that activate the small GTP-binding protein Rap1
- The cyclic nucleotide-gated channels (CNGCs)
These various effectors are then responsible for carrying out the cyclic AMP signaling functions that include control of metabolism, gene transcription, and ion channel activity. In many cases, these functions are modulatory in that cyclic AMP often acts to adjust the activity of other signaling pathways and thus has a central role to play in the cross-talk.