Presynaptic facilitation

Hawkins, R. D., Abrams, T. W., Carew, T. J., and Kandel, E. R. (1983) A cellular mechanism of classical conditioning in aplysia Activity-dependent amplification of presynaptic facilitation. Science, 219 400-405. 

In addition to their peripheral functions, including presynaptic facilitation of noradrenaline release, p-adrenoceptors play a role in regulating numerous functions of the central nervous system, including sympathetic tone, learning and memory, mood, and food intake. Mice lacking dopamine p-hydroxylase or p-adrenoceptor subtypes were used to study the involvement in memory functions. Noradrenaline acting at p, -receptors was found to be essential for retrieval of contextual and spatial memory, but it was not necessary for retrieval of emotional memories (Murchison... 

Intracellular Events in A2 Receptor-Mediated Presynaptic Facilitation.346... 

Fig. 2 Mechanisms involved in presynaptic facilitation through A2 adenosine receptors. A2A and A2B adenosine receptors (A2aAR, A2B AR), by coupling to Gs, activate adenylate cyclase and protein kinase A (PKA). This may (1) influence SNARE proteins or (2) enhance calcium currents through P-type voltage-sensitive calcium channels (P-VSCC). A2aAR may also couple to Gq, leading to activation of a protein kinase C (PKC) pathway. This may (3) enhance calcium currents through N-VSCC, (4) influence SNARE proteins, (5) promote the PKA pathways or (6) remove an ongoing Gj/0 mediated inhibition of release.

Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci 23 3136-3144... 

Fig. 3A, B Tonic release of anandamide presynaptically facilitates glutamatergic synaptic transmission in substantia nigra by activating TRPVl receptors. A Anandamide AEA, 30 pM) increases the rate (leftward shift in the cumulative distribution ofthe inter-event interval), but has no effect on the amplitude distribution of spontaneous EPSCs (sEPSCs). B The TRPVl antagonist iodoresiniferatoxin (IRTX, 300 nM) decreases the rate (rightward shift in the cumulative distribution of the inter-event interval), but has no effect on the amplitude distribution of sEPSCs. Insets show raw traces of sEPSCs before (control) and during AEA and IRTX. (Modified from Marinelli et al. 2003, by permission)...

Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi, G., and Mercuri, N.B. (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors, J. Neurosci., 23 3136-44. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Tyrosine phosphorylation plays an important role in synaptic transmission and plasticity. Evidence for this role is that modulators of PTKs and PTPs have been shown to be intimately involved in these synaptic functions. Among the various modulators of PTKs, neuro-trophins have been extensively studied in this regard and will be our focus in the following discussion (for details of growth factors, see Ch. 27). BDNF and NT-3 have been shown to potentiate both the spontaneous miniature synaptic response and evoked synaptic transmission in Xenopus nerve-muscle cocultures. Neurotrophins have also been reported to augment excitatory synaptic transmission in central synapses. These effects of neurotrophins in the neuromuscular and central synapses are dependent on tyrosine kinase activities since they are inhibited by a tyrosine kinase inhibitor, K-252a. Many effects of neurotrophins on synaptic functions have been attributed to the enhancement of neurotransmitter release BDNF-induced increase in neurotransmitter release is a result of induced elevation in presynaptic cytosolic calcium. Accordingly, a presynaptic calcium-depen-dent phenomenon - paired pulse facilitation - is impaired in mice deficient in BDNF. 

Kainate receptors mediate a depression of evoked excitatory synaptic transmission in areas CA1 (40,88-90) and CA3 (35,37,91,92) of the hippocampus. There is strong evidence that in area CA1 the locus of this effect is presynaptic. Thus, activation of kainate receptors depresses release of L-glutamate from synaptosomes (88) and depresses both NMDA and AMPA receptor-mediated components of the evoked EPSC in parallel (88,90). Furthermore, the effects of kainate receptor activation on excitatory synaptic transmission in CA1 are associated with changes in presynaptic Ca2+ (89), an increase in paired-pulse facilitation (35,88,89), and a reduction in quantal content, as assessed using 1/CV2, but no change in mEPSC amplitude (90). 

Facilitatory actions of presynaptic kainate receptors (82,88) were long overshadowed by the pronounced inhibitory effects of kainate receptor agonists on both gluta-matergic and GABAergic transmission. Recently, facilitation of synaptic transmission via activation of a presynaptic kainate receptors has been described in the GABAergic synapses in area CA1 (86), in the spinal cord (99), and probably most thoroughly, in the mossy-hber synapse in area CA3 (39,77,100). 

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. 

In contrast to the metabotropic effects described for presynaptic kainate receptors in CA1 (90,94), the effects of kainate in CA3 appear to be mediated by direct depolarization of the presynaptic terminals. The kainate-induced facilitation is not sensitive to antagonists of other receptors (e.g., GABAb), and can be mimicked by elevating the extracellular potassium concentration (77,100). It has been proposed that the facilitation is owing to increased calcium influx that is induced by modest depolarization of the terminals by kainate receptors, whereas a strong depolarization, in response to activation of a larger receptor population, causes the sodium channels to inactivate and thereby depresses transmission (77,84,88,100-102). 

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... 

Lauri, S. E., Delany, C Clarke, V.R J., Bortolotto, Z. A., Omstein, P. L Isaac, J. T. R., and Collingridge, G. L. (2001a) Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fibre synapses. 

Schmitz, D., Mellor, J., and Nicoll, R. A. (2001) Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291, 1972-1976. 

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