Synaptic function

There is no shortage of AEDs (Fig. 16.7) but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above (Fig. 16.6) for the control of epileptic seizures (see Meldrum 1996 Upton 1994). The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy (some drugs are inactive in certain forms) but also what side-effects they have—many are sedative — how they interact with other drugs and how often they need to be taken. Compliance is a problem over a long period if dosing is required more than once a day. It is probably acceptable in reality, if not scientifically, to divide the drugs into old-established AEDs and new AEDs. Only the latter have been developed chemically to modify the known synaptic function of the amino acids. 

NEUROTRANSMITTERS IN MEMORY PROCESSING AND APPROPRIATE SYNAPTIC FUNCTION... 

Nakagawa, T., Putai, K., Lashuel, H. A., Lo, I., Okamoto, K., Walz, T., Hayashi, Y., and Sheng, M. (2004). Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44, 453—467. 

Calmodulin, a calcium binding protein, is involved in Ca2+-dependent regulation of several synaptic functions of the brain synthesis, uptake and release of neurotransmitters, protein phosphorylation and Ca+2 transport. It reacts with TET, TMT and TBT which then inactivates enzymes like Ca+2-ATPase and phosphodiesterase. In vitro studies indicated TBT was greater at inhibiting calmodulin activity than TET and TMT, whereas in vivo the order was TET > TMT > TBT. This may be due to the greater detoxification of TBT (66%) in the liver before moving to other organs30,31. 

Bullens, R. W., O Hanlon, G. M., Wagner, E. etal. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. /. Neurosci. 22 6876-6884, 2002. 

Sala, C., Piech, V., Wilson, N. R. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31 115-130, 2001. 

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. 

Henderson, J. T., Georgiou, J., Jia, Z. P. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32 1041-1056, 2001. 

Reports that AA is released primarily by G-protein-mediated PLA2 activation remain to be confirmed [84, 85]. In addition, modulation of PLA2 by Ca2+ and protein kinase needs to be better defined. It is clear that NMDA receptor activation promotes the release of AA [86], and that a variety of eicosanoids are then generated (Fig 33-2,33-3). The modulatory events that channel AA towards specific eicosanoids are not understood. The endocannabinoid family of lipid messengers will remain an active focus of interest because of the growing evidence of their actions in synaptic function, learning, memory, and other forms of behavior [56,87]. 

These findings were confirmed and extended by in vitro electrophysiological studies of slices from normal animals that revealed that subtle (e.g. 20%) reductions of inhibitory synaptic function could lead to epileptiform activity. Importantly, activation of excitatory synapses is often pivotal in the expression of a seizure in distinct models in vitro. In addition to these important pharmacological observations, electrophysiological analyses of individual neurons during a partial seizure revealed that neurons undergo a massive depolarization and fire action potentials at high frequencies (Fig. 37-1) [3], This pattern of... 

Clements, J. D. (1996) Transmitter timecourse in the synaptic cleft its role in central synaptic function. Trends Neurosci. 19,163-171. 

There is now a growing interest in proteomic studies of brain synapses. Recent studies have revealed a high molecular complexity in the pre- and postsynaptic areas, with thousands of proteins [6]. An important investigation for the future is to identify posttranslational modifications, miscoded as well as misfolded proteins, likely to have an impact on different aspects of synaptic function as a response to the environment as well as to the lifestyle. The first challenge is to identify and quantify the presence and variation of different proteins in key structures of the pre- and postsynaptic areas in order to relate protein structures to synaptic function. Recently, a new model has been presented describing the molecular complexity of the synapse with important aspects in emotions, thinking, memory, and consciousness [7] (Fig. 17.2). 

Aitken PG, Braitman DJ. 1989. The effects of cyanide on neural and synaptic function in hippocampal slices. Neurotoxicology 10 239-248. 

Although these animal models show abnormalities, they fail to reproduce the PD phenotype. Still, they suggest a role for Parkin in synaptic function and maintenance of mitochondrial integrity. 

Based on the results from various studies described above, it is clear that the failure of the ubiquitin-proteasome pathway ultimately contributes to cell death or degeneration in polyglutamine diseases. This process is probably progressive. Initial formation of aggregates with proteins with long polyglutamine stretches perhaps impairs proteasome activity, which in turn leads to accumulation of more protein aggregates, and thus misfolded proteins could build up in the cell. Initially, however, impairment of the proteasome probably has an effect on synaptic properties of the neuron because as discussed elsewhere in this chapter, proteasome activity in various subcellular compartments of the neuron is essential for normal synaptic function and plasticity. 

Recent evidence indicates that PD might affect synaptic function adversely. In parkin-deficient mice, higher stimulation of corticostriatal afferents were required to evoke EPSPs in striatal spiny neurons suggesting that excitability of spiny neurons was reduced." Also, parkin, which is an ubiquitin ligase" has been shown to interact with and ubiquitinate synaptotagmin XI." " ... 

Rapoport, S.I. (2003) Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease. Neurotox. Res., 5, 385-398. 

Fragile Xsyndrome is an X-IInked disorder arising from inactivation ofFMRI, a gene that encodes a protein critical for synaptic function. 

The influence of BDNF regulation of synaptic function on behaviour has still to be fully determined. Rats treated with antibodies to BDNF (icv) were signihcantly impaired in a spatial learning task (Mu et ah, 1999). Levels of BDNF expression in CAl were rapidly and selectively increased following contextual fear conditioning, a form of learning also dependent on the hippocampus (Hall et ah, 2000). 

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