Over the past 60 years, a large number of selective neurotoxins were discovered and developed, making it possible to animal-model a broad range of human neuropsychiatric and neurodevelopmental disorders. In this paper, we highlight those neurotoxins that are most commonly used as neuroteratologic agents, to either produce lifelong destruction of neurons of a particular phenotype, or a group of neurons linked by a specific class of transporter proteins (i.e., dopamine transporter) or body of receptors for a specific neurotransmitter (i.e., NMDA class of glutamate receptors). Actions of a range of neurotoxins are described: 6-hydroxydopamine (6-OHDA), 6-hydroxydopa, DSP-4, MPTP, methamphetamine, IgG-saporin, domoate, NMDA receptor antagonists, and valproate. Their neuroteratologic features are outlined, as well as those of nerve growth factor, epidermal growth factor, and that of stress. The value of each of these neurotoxins in animal modeling of human neurologic, neurodegenerative, and neuropsychiatric disorders is discussed in terms of the respective value as well as limitations of the derived animal model. Neuroteratologic agents have proven to be of immense importance for understanding how associated neural systems in human neural disorders may be better targeted by new therapeutic agents.

Neurotoxlns represent unique chemical tools, providing a means to 1) gain insight into cellular mechanisms of apopotosis and necrosis, 2) achieve a morphological template for studies otherwise unattainable, 3) specifically produce a singular phenotype of denervation, and 4) provide the starting point to delve into processes and mechanisms of nerve regeneration and sprouting. There are many other notable uses of neurotoxins in neuroscience research, and ever more being discovered each year. The objective of this review paper is to highlight the broad areas of neuroscience in which neurotoxins and neurotoxicity mechanism come into play. This shifts the focus away from neurotoxins per se, and onto the major problems under study today. Neurotoxins broadly defined are used to explore neurodegenerative disorders, psychiatric disorders and substance use disorders. Neurotoxic mechanisms relating to protein aggregates are indigenous to Alzheimer disease, Parkinson's disease. NeuroAIDS is a disorder in which microglia and macrophages have enormous import. The gap between the immune system and nervous system has been bridged, as neuroinflammation is now considered to be part of the neurodegenerative process. Related mechanisms now arise in the process of neurogenesis. Accordingly, the entire spectrum of neuroscience is within the purview of neurotoxins and neurotoxicity mechanisms. Highlights on discoveries in the areas noted, and on selective neurotoxins, are included, mainly from the past 2 to 3 years.

Neurotoxins, in the general sense, represent novel chemical structures which when administered in vivo or in vitro, are capable of producing neuronal damage or neurodegeneration - with some degree of specificity relating to neuronal phenotype or populations of neurons with specific characteristics (.e., receptor type, ion channel type, astrocyte-dependence, etc.). The broader term 'neurotoxin' includes this categorization but extends the term to include intra- or extracellular mediators involved in the neurodegenerative event, including necrotic and apoptotic factors. Moreover, as it is recognized that astrocytes are essential supportive satellite cells for neurons, and because damage to these cells ultimately affects neuronal function, the term 'neurotoxin' might reasonably be extended to include those chemical species which also adversely affect astrocytes. This review is intended to highlight developments that have occurred in the field of 'neurotoxins' during the past 5 years, including MPTP/MPP+, 6-hydroxydopamine (6-OHDA), meth-amphetamine; salsolinol; leukoaminochrome-o-semi-quinone; rotenone; iron; paraquat; HPP+; veratridine; soman; glutamate; kainate; 3-nitropropionic acid; peroxynitrite anion; and metals (copper, manganese, lead, mercury). Neurotoxins represent tools to help elucidate intra- and extra-cellular processes involved in neuronal necrosis and apoptosis, so that drugs can be developed towards targets that interrupt the processes leading towards neuronal death.

Die integralen Vesikelmembranproteine Synaptophysin und Synaptobrevin interagieren in adulten Neuronen. Zusätzlich bildet Synaptobrevin mit den Plasmamembranproteinen Syntaxin und synaptosome-associated protein 25kDa (SNAP25) den SNAP-Rezeptor (SNARE)-Proteinkomplex, der Voraussetzung für die Fusion zwischen synaptischen Vesikeln und präsynaptischer Membran ist. Mit Synaptophysin interagierendes Synaptobrevin bindet jedoch nicht an den SNARE-Proteinen. Es wird daher vermutet, dass der Synaptophysin/Synaptobrevin-Komplex eine Art Reservepool für Synaptobrevin bei erhöhter neuronaler Aktivität darstellt und die Verfügbarkeit von Synaptobrevin während der Exozytose reguliert. Mit verschiedenen Ansätzen wurde versucht, den auf dem Vesikel befindlichen Komplex genauer zu charakterisieren und in seiner Funktion näher zu beschreiben. Nach Stimulation mit exozytosevermittelnden Substanzen dissoziierte der Synaptophysin/ Synaptobrevin-Komplex, sowohl unter nativen Bedingungen als auch bei Blockierung des finalen Fusionsereignisses. Dieser Prozess war calciumabhängig, konnte jedoch nicht durch die direkte Wirkung von Calcium ausgelöst werden. Die Untersuchung des Komplexes mit Hilfe von clostridialen Neurotoxinen zeigte, dass Synaptobrevin bevorzugt in Bindung an Synaptophysin und als Dimer gespalten wurde. Die Spaltung des SNARE-Proteins SNAP25 hatte keinen Einfluss auf die Komplexbildung. Die Verringerung des Cholesterolgehaltes der Membran führte zur Abnahme der Interaktion von Synaptophysin und Synaptobrevin, umgekehrt zeigte sich ein Anstieg bei zusätzlicher Cholesterolapplikation. In weiteren Experimenten konnte der C-terminale Teil des Synaptobrevins als für die Bindung zu Synaptophysin entscheidende Abschnitt identifiziert werden. Weiterhin konnte die erfolgreiche Translokation von rekombinanten Konstrukten aus Botulinumtoxin D und einem angekoppelten funktionstüchtigen Protein ins Zytosol gezeigt werden. / The vesicle associated membrane proteins synaptophysin and synaptobrevin interact in ma-ture neurones. Additionally synaptobrevin forms a complex with the plasma membrane pro-teins syntaxin and synaptosome-associated protein 25kDa (SNAP25), better known as the SNAP-Receptor (SNARE) complex, which is a prerequisite for fusion of the presynaptic and vesicle membranes. These two protein complexes however are mutually exclusive. It is as-sumed that the synaptophysin/synaptobrevin complex resembles a reserve pool for synapto-brevin and regulates the availability of synaptobrevin for the fusion process in case of in-creased synaptic activity. Different approaches where chosen to characterize this protein complex and to examine its function in more detail. After excessive stimulation the synaptophysin/synaptobrevin complex dissociates, even when the final fusion process is blocked. This step was dependent on the presence of cal-cium, though it could not be triggered directly by calcium administration. When using clos-tridial neurotoxins, synaptobrevin was preferentially cleaved in its homodimeric form and in the complex with synaptophysin. Cleavage of SNAP25 had no effect on the complex forma-tion. Depletion of cholesterol content decreases the interaction of synaptophysin with synap-tobrevin, while cholesterol treatment increases interaction. Further experiments indicated that synaptophysin binds to the the carboxy-terminal transmembrane part of synaptobrevin. Fur-thermore it could be shown that proteins attached to botulinum toxin can be delivered to the cytosol of neuronal cells, being fully active.

There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin "nerve growth factor" (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an "immunosympathectomy" and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a "selective" neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson's disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as "selective neurotoxins," despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become "selective" neurotoxins; nonspecific cytotoxins can become classified as "selective" neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as "selective" neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins.