Synapse presynaptic events

Chemical transmission between nerve cells involves multiple steps 167 Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells 168 A variety of methods have been developed to study exocytosis 169 The neuromuscular junction is a well defined structure that mediates the presynaptic release and postsynaptic effects of acetylcholine 170 Quantal analysis defines the mechanism of release as exocytosis 172 Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis 174 Presynaptic events during synaptic transmission are rapid, dynamic and interconnected 175... 

Presynaptic events during synaptic transmission are rapid, dynamic and interconnected. The time between Ca2+ influx and exocytosis in the nerve terminal is very short. At the frog NMJ at room temperature, 0.5-1 ms elapses between the depolarization of the nerve terminal and the beginning of the postsynaptic response. In the squid giant synapse, recordings can be made simultaneously in the presynaptic nerve terminal and in the postsynaptic cell. Voltage-sensitive Ca2+ channels open toward the end of the action potential. The time between Ca2+ influx and the postsynaptic response as measured by the postsynaptic membrane potential is 200 ps (Fig. 10-7). However, measurements made with optical methods to record presynaptic events indicate a delay of only 60 ps between Ca2+ influx and the postsynaptic response at 38°C [21]. 

Once the neurotransmitter is in the synapse, several events may occur. It may (1) diffuse across the synapse and bind to a receptor on the post-synaptic membrane, (2) diffuse back to the presynaptic neuron and bind to a presynaptic receptor causing modulation of neurotransmitter release, (3) be chemically altered by an enzyme in the synapse, or (4) be transported into a nearby cell. For the chemical message to be passed to another cell, however, the neurotransmitter must bind to its protein receptor on the postsynaptic side. The binding of a neurotransmitter to its receptor is a key event in the action of all neurotransmitters. 

One of the consequences of this rapid increase in protein synthetic capacity in VMN neurons is that E increases the number of spines on dendrites and increases the density of synapses in the VMN. These events occur cyclically during the estrous cycle of the female rat. Dots indicate presynaptic vesicles containing neurotransmitter. 

Once the electrical signal has arrived at a chemical synapse (see Fig 4.2) a cascade of events is triggered with the arrival of an electrical impulse (an action potential), a chemical compound known as a neurotransmitter is released from the presynaptic side into the synaptic cleft. The released neurotransmitter then reaches the membrane of the second cell (postsynaptic membrane) where it interacts with a macromolecule, a so-called receptor. It is this neurotransmitter receptor interaction that triggers another cascade of (chemical) reactions within the second cell and this ultimately leads to the generation of an electrical signal within this cell. This signal then is transferred along this second cell s axon towards another synapse. 

A synaptic vesicle cycle. The number of synaptic vesicles in a single synapse in the brain varies from fewer than 100 to several hundred. In specialized synapses there may be thousands. However, at any moment only a fraction of the total are in the "active zone," often aligned along the presynaptic membrane (Fig. 30-20A) or in specialized ribbons such as those in Fig. 30-10B. The vesicles are normally reused repeatedly, undergoing a cycle of filling with neurotransmitter, translocation to the active zone, ATP-dependent priming, exocytosis with release of the neurotransmitter into the synaptic cleft, coating with clathrin, endocytosis, and acidification as outlined in Fig. 30-20B.554-557 The entire cycle may be completed within 40-60 s to avoid depletion of active vesicles.558 559 A key event in the cycle is the arrival of an action potential at the presynaptic neuron end. 

Similar events occur at synapses where the presynaptic cell releases an inhibitory neurotransmitter such as y-aminobutyrate, except that here the receptor typically provides a pore that is specific for K+ or Cl" ions. K+ efflux or Cl " influx hyperpolarizes the plasma membrane to a potential more negative than the resting potential, opposing the depolarization induced by stimulatory neurotransmitters. 

The third dimension of chemical neurotransmission is function, namely that cascade of molecular and cellular events set into action by the chemical signaling process. First come the presynaptic and then the postsynaptic events. An electrical impulse in the first, or presynaptic, neuron is converted into a chemical signal at the synapse by a process known as excitation-secretion coupling. 

This reuptake pump takes an active part in the neurotransmission process, which begins with the firing of the presynaptic neuron and release of neurotransmitter (Fig. 2—23). The neurotransmitter diffuses across the synapse, binds its neurotransmitter receptors selectively, and triggers all the subsequent events that translate that chemical message into another neuronal impulse in the postsynaptic neuron, activate postsynaptic genes, and regulate various cellular functions in the target neuron. The neurotransmitter then diffuses off its receptor and can be destroyed by enzymes or transported back into the presynaptic neuron. 

The chemical synapse is a highly specialized structure that has evolved for exquisitely controlled voltage-dependent secretions. The chemical messengers, stored in vesicles, are released from the presynaptic cell following the arrival of an action potential that triggers the vesicular release into the presynaptic terminal. Once released from the vesicles, the transmitter diffuses across a narrow synaptic cleft, then binds to specific receptors in the postsynaptic cell, and finally initiates an action potential event in the nerve-muscle cell membrane by triggering muscle contractions. 

Synaptic neurotransmission in brain occurs mostly by exocytic release of vesicles filled with chemical substances (neurotransmitters) at presynaptic terminals. Thus, neurotransmitter release can be detected and studied by measuring efflux of neurotransmitters from synapses by biochemical methods. Various methods have been successfully employed to achieve that, including direct measurements of glutamate release by high-performance liquid chromatography of fluorescent derivatives or by enzyme-based continuous fluorescence assay, measurements of radioactive efflux from nerve terminals preloaded with radioactive neurotransmitters, or detection of neuropeptides by RIA or ELISA. Biochemical detection, however, lacks the sensitivity and temporal resolution afforded by electrophysiological and electrochemical approaches. As a result, it is not possible to measure individual synaptic events and apply quantal analysis to verify the vesicular nature of neurotransmitter release. 

In principle, the activation of a presynaptic ionotropic receptor may either increase or decrease the amount of transmitter being released. However, the effect may depend on the situation prior to the activation of the receptor. In this context one has to mention that transmitter release occurs either due to spontaneous fusion of vesicles with the plasma membrane or as a consequence of an event that triggers increases in the intracellular Ca2+ concentration at the active zone where vesicle exocytosis takes place. The Ca2+ concentrations required to promote exocytosis towards maximal rates lie between approximately 10 and 100 pM (Augustine 2001 Schneggenburger and Neher 2005), depending on the synapse being investigated. These two types of transmitter release are usually named spontaneous and stimulated (or stimulation-evoked) release, respectively. 

Neurotransmission at chemical synapses is carried out by a complex sequence of events. Initially, an action potential arrives at the presynaptic terminal, inducing a rapid, transient influx of Ca2+ locally ( Figure 2.4-1). 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

The regions of the presynaptic membrane where fusion of vesicles and the plasmalemma occur are limited to what has been termed the active zones. Closely associated with these active zones are what electron microscopists believe may be clusters of calcium ionophores necessarv for the entry of Ca + for the initiation of exocytotic release. Other morphological entities at the active zone have also been identified, but their physiological role in transmitter release has not been elucidated. It should be noted that numerous freeze-fracture micrographs taken of active synapses reveal many more vesicle fusions than would be predicted for one or two release events. These observations are not consistent with the one vesicle-one quantum hypothesis that was briefly discussed earlier. To date, no explanation for the discrepancy between the number of vesicles and the number of quanta released has been proposed except to suggest that the vesicle, in fact, only releases a fraction of the quantum, which has been termed a microquantum. 

A number of criteria must be met to conclude that a cyclic nucleotide is involved in a postsynaptic event. First of all, electrical stimulation of the presynaptic neuron or microiontophoresis of the putative neurotransmitter at the synapse should increase the level of cyclic nucleotide. This increase should be blocked by receptor antagonists or low Ca, which would prevent neurotransmitter release after electrical stimulation. Second, the pres-... 

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