Presynaptic plasticity

A complete discussion of presynaptic modulation and plasticity of release is beyond the scope of this chapter. Instead, three exemplary forms of presynaptic plasticity will be discussed because of their importance for the pharmacology of neurotransmitter release. 

Wiedemann C, Schafer T, Burger MM et al (1998) An essential role for a small synaptic vesicle-associated phosphatidylinositol 4-linase in meurotransmitter release. J Neurosci 18 5594-5602 Wierda KD, Toonen RF, de WH et al (2007) Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 54 275-90 Willars GB (2006) Mammalian RGS proteins multifunctional regulators of cellular signalling. Semin Cell Dev Biol 17 363-76... 

Bogen IL, Jensen V, Hvalby O, Walaas SI. 2009. Synapsin-dependent development of glutamatergic synaptic vesicles and presynaptic plasticity in postnatal mouse brain. Neuroscience 158 231-241. 

Rimla [55]. This form of PKA-dependent presynaptic plasticity is also observed in cerebellum and at corticothalamic and corticostriatal synapses [53]. Synaptic plasticity also involves adaptive decreases in synaptic strength [56]. Of these, the archetype is NMDA receptor-dependent long-term depression (LTD) in the hippocampus [57], which appears to be critically dependent on the dephosphorylation of PKA substrates. Of particular significance is the selective dephosphorylation of the PKA site Ser845 on GluRl which decreases the probability of AMPA receptor channel opening and increases AMPA receptor endocytosis [58]. 

Long-term potentiation (LTP) is a synaptic plasticity phenomenon that corresponds to an increase in the synaptic strength (increase in the post-synaptic response observed for the same stimulation of the presynaptic terminals) observed after a high frequency stimulation (tetanus) of the afferent fibres. This increased response is still observed hours and even days after the tetanus. The phenomenon is often observed at glutamatergic synapses and involves, in most cases, the activation of the V-methyl D-aspartate (NMDA) subtype of ionotropic glutamate receptors. 

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. 

Finally, this section has focused almost entirely on axonal transport, but dendritic transport also occurs [25]. Since dendrites usually include postsynaptic regions while most axons terminate in presynaptic elements, the dendritic and axonal transport each receive a number of unique proteins. An added level of complexity for intraneuronal transport phenomena is the intriguing observation that mRNA is routed into dendrites where it is implicated in local protein synthesis at postsynaptic sites, but ribosomal components and mRNA are largely excluded from axonal domains [26]. Regulation of protein synthesis in dendritic compartments is an important mechanism is synaptic plasticity [27,28]. The importance of dendritic mRNA transport and local protein synthesis is underscored by the demonstration that the mutation associated with Fragile X syndrome affects a protein important for transport and localization of mRNA in dendrites [27, 29], Similar processes of mRNA transport have been described in glial cells [30]. 

Endocannabinoids serve as retrograde messengers. They are released by postsynaptic neurons and act on presynaptic CB1 receptors on neighboring nerve terminals. Retrograde signaling by endocannabinoids is essential for many forms of synaptic plasticity that are initiated by postsynaptic depolarization and increased postsynaptic intracellular Ca2+> but expressed as a presynaptic decrease in the probability of transmitter release. Examples include some forms of long-term depression (LTD see Ch. 53) at GABA... 

Kamiya, H Ozawa, S and Manabe, T. (2002) Kainate receptor-dependent short-term plasticity of presynaptic Ca2 influx at the hippocampal mossy hber synapses../. Neurosci. 22(21), 9237-9243. 

Kamiya, H. (2002) Kainate receptor-dependent presynaptic modulation and plasticity. 

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