, 1994; Bering et al., 1997; Freund and Buzsáki, 1996). Hippocampal pyramidal cells, often learn more used as a primary model for the study of glutamatergic neurons, are reported to express peptides, for instance cholecystokinin (Wyeth et al., 2012), particularly in models of brain disease such as epilepsy. From an evolutionary perspective, peptide synthesis in invertebrates may give us clues as to the parallel in vertebrates. In Aplysia, every identified motorneuron was found

to contain one or more of a number of different peptide modulators ( Church and Lloyd, 1991). Scientists have a keen insight into the temporal sequence and many of the molecules involved in the release of fast neurotransmitters at presynaptic specializations (Südhof, 2012). Release of neuropeptides, mostly from nonsynaptic Galunisertib concentration sites, has received considerably less attention than fast transmitter release; neuropeptide release from dense core vesicles (DCVs) may require a unique set of proteins that regulate transport and release (Sieburth et al., 2005, 2007). Mammalian neuropeptide release has been most thoroughly investigated in the neurohypophysis where axons arising from magnocellular neurons of the hypothalamic paraventricular

and supraoptic nuclei converge to release vasopressin or oxytocin into the vascular system. Vasopressin plays a key role in water homeostasis and water reabsorption in the kidney, and PDK4 oxytocin acts to evoke milk release during lactation. The neurohypophysis provides a good model to study release, as it contains a high density of large axon terminals filled with large (180–200 nm diameter) dense core neurosecretory vesicles, providing a relatively high and measurable

amount of peptide release. Classical work here has shown that the amount of neuropeptide released per spike increases with spike frequency up to a point (Dreifuss et al., 1971; Gainer et al., 1986) and that spike bursts followed by intervals of silence are particularly effective at releasing oxytocin or vasopressin (Dutton and Dyball, 1979; Bicknell and Leng, 1981; Cazalis et al., 1985). A mechanism that has been reported to underlie this enhanced-release phenomenon is the increase in cytoplasmic calcium in axon terminals induced by spike bursts which may be a key to the enhanced probability of DCV exocytosis (Bondy et al., 1987; Jackson et al., 1991; Muschol and Salzberg, 2000). Although the neurohypophysis provides a useful model for studying neuropeptide release, there are some serious differences between peptide release from large neurohypophyseal boutons filled with large neurosecretory vesicles and peptide release from the more common small axon terminals that may possess medium size (100 nm diameter) neuropeptide-containing DCVs; large DCVs have been estimated to contain 60,000 (Dreifuss, 1975) or 85,000 (Nordmann and Morris, 1984) molecules of oxytocin or vasopressin.