Presynaptic fibers

Kainate (200 nM) renders the mossy-fiber axons more excitable, as evidenced by an increase in the presynaptic fiber volley as well as lowered threshold for antidromic action potentials. At the same time, a kainate-induced suppression of synaptic transmission and depression of presynaptic calcium influx was observed (92). In contrast, application of very low concentrations of kainate (50 nM) facilitates synaptic transmission at the mossy fibers (77,100). The kainate-induced facilitation is blocked by LY382884, suggesting a role for GLUK5-containing receptors (77). However, only depression of transmission has been observed with ATPA (35). Thus, the facilitatory and depressory effects of kainate could be mediated by different receptor populations that have distinct pharmacological properties. 

An action potential in the presynaptic fiber propagates into the synaptic terminal and activates voltage-sensitive calcium... 

When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability. Changing the stimulus intensity to the pathway, and therefore the number of presynaptic fibers activated, results in a graded change in the size of the depolarization. When a sufficient number of excitatory fibers are activated, the excitatory postsynaptic potential depolarizes the postsynaptic cell to threshold, and an all-or-none action potential is generated. 

An action potential in the presynaptic fiber propagates into the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal (Figure 6-3). The calcium channels responsible for the release of transmitter are generally resistant to the calcium channelblocking agents discussed in Chapter 12 Vasodilators the Treatment of Angina Pectoris (verapamil, etc) but are sensitive to blockade by certain marine toxins and metal ions (Tables 12-4 and 21-1). Calcium flows into the terminal, and the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The transmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic... 

Sites of drug action. Schematic drawing of steps at which drugs can alter synaptic transmission. (7) Action potential in presynaptic fiber (2) synthesis of transmitter (3) storage (4) metabolism (5) release (6) reuptake (7) degradation (8) receptor for the transmitter (9) receptor-induced increase or decrease in ionic conductance. 

Certain proteins that appear to be present only in the synaptic plasmalem-ma have been shown to be phosphorylated specifically by cAMP-dependent kinase. Termed proteins la and Ib, these proteins are rapidly phosphorylated (in less than 5 sec) by electrical stimulation of presynaptic fibers and by application of the neurotransmitter believed to be released by the presynaptic neuron. Depolarizing agents, such as potassium and veratridine, when applied to the postsynaptic fibers, cause an enormous increase in the phosphorylation of proteins la and Ib. Dibutyryl cAMP and 8-bromo cAMP both mimic the actions of the neurotransmitters, as do phosphodiesterase inhibitors. The function of these proteins is at present unknown. 

Figure 21-2. Sites of CNS drug action. Drugs may alter (1) the action potential in the presynaptic fiber (2) the synthesis of transmitter (3) the storage of transmitter (4) the metabolism of transmitter within the nerve ending (5) the release of transmitter (6) the reuptake or (7) extracellular disposition of transmitter (8) the postsynaptic receptor or (9) the postsynaptic effects that follow receptor activation. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

Fig. 12. The relation between field epsp amplitude and perforant path stimulus intensity in young ( ) and old (O) rats is shown for the in vivo (A) and in vitro (D) preparations. For comparison, stimulus intensity is expressed as the product of current and duration since these two parameters were varied differently in the two preparations. For the in vivo experiment, response wave forms were averaged across animals within the young (B) and old (C) groups. Superimposed traces at the various stimulus levels recorded simultaneously from the granule layer (E) and the molecular layer (F) are shown from a single slice preparation. The dashed lines in B, C, and E indicate the time of measurement of the field epsp (2 msec after stimulus onset). The sharp negative deflections in B, C, and E are population spikes (asterisks), whereas the early negative deflection in F represents the presynaptic fiber response (arrow). (From Barnes and McNaughton, 1980.)...

Figure 8.2 The endogenous analgesic system. The three major components of the endogenous analgesic system include the periaqueductal gray matter in the midbrain nucleus raphe magnus in the medulla and pain inhibitory complex in the dorsal horns of the spinal cord. This system causes presynaptic inhibition of pain fibers entering the spinal cord. The binding of enkephalin to opioid receptors on the pain fibers prevents release of the neurotransmitter, substance P. As a result, the pain signal is terminated in the spinal cord and does not ascend to higher centers in the CNS.

A second type of NMDA-receptor-independent LTP exists in the mossy-fiber pathway at the dentate granule cell-to-CA3 pyramidal cell synapse [19]. This form of LTP, termed mossy fiber-CA3 LTP, is believed to involve PKA activation in the presynaptic cell which leads to increased neurotransmitter release. However, the exact induction mechanism is not yet clear. 

There is growing evidence to suggest that, within the hippocampus, kainate and AIPA may depress fast excitatory transmission by distinct mechanisms. For example, in area CA3, kainate exerts its effects via an action on presynaptic mossy-fiber excitability (37,92), whereas ATPA is suggested to act indirectly via an increase in... 

Kainate receptors have recently been implicated in the induction of EIP in the mossy fibers (49,85). Unlike EIP in the area CA1, induction of mossy-fiber EIP is independent of NMDA-receptor activation and involves presynaptic mechanisms (105). Synaptic activation of the facilitatory presynaptic receptor can account for the role of KA receptors in the induction of mossy-fiber LIP by maintaining a high level of release during high-frequency transmission (77). Furthermore, following induction of LTP, the presynaptic kainate receptor-mediated facilitation of synaptic transmission is lost, suggesting that the mechanism by which presynaptic kainate receptors facilitate... 

Schmitz, D., Frerking, M., and Nicoll, R. A. (2000) Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 27,327-338. 

Sharma G, Ajayaraghavan S (2003) Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron 38 929-939 Sharma G, Grybko M, Vijayaraghavan S (2008) Action potential-independent and nicotinic receptor-mediated concerted release of multiple quanta at hippocampal CA3-mossy fiber synapses. J Neurosci 28 2563-2575... 

By activating presynaptic autoreceptors in brain stem locus ceruleus neurons (where most noradrenergic fibers have their origin), clonidine reduces norepine-pherine release and turnover. This inhibitory effect on noradrenergic locus ceruleus neurons, as well as direct effects on thalamic receptors, are most likely responsible for the sedative effects of clonidine (Berridge and Foote, 1991 Buzsaki et ah, 1991). 

Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6-4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers. 

Diagram of the structures involved in the stretch reflex arc. I is an inhibitory interneuron E indicates an excitatory presynaptic terminal la is a primary intrafusal afferent fiber Ca2+ denotes activator calcium stored in the sarcoplasmic reticulum of skeletal muscle RyR channels indicates the Ca2+ release channels. 

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