Expression of AVP and OT in the PVN and SON occurs in strictly separate neuronal populations, principally as a result of differential expression at the mRNA level that seems to be regulated by check details cis-elements (Gainer, 2012). In contrast to humans, the development of PVN and SON nuclei is late in rodents. Synthesis of AVP in rats starts between day 16 and 18 in utero and that of OT few days after birth (Lipari et al., 2001). Both are stored in secretory

granules or vesicles along with their respective carrier proteins, the neurophysins. Neurophysins for the two peptides are of similar molecular weight (10 kDa) with a high percentage of cysteine residues linked by disulfide bridges. Together with AVP/OT, they are synthesized in the cell body as part of a common precursor protein that contains a glycopeptide at the amino end, subsequently AVP/OT, and neurophysin at its carboxy end. Significant processing of this prohormone partly takes place in the granules that contain the enzymes for posttranslational processing during their transport

to the axon terminal. Thus, for the case of OT, synthesized as nonglycosylated protein, it undergoes endoproteolytic cleavage by the convertase magnolysin to OT-Gly-Lys-Arg (OT-GKR), OT-Gly-Lys (OT-GK), and OT-Gly (OT-G, also known as OT-X) (Brownstein et al., 1980; Burbach et al., 2001). The latter is converted by an alpha-amidating enzyme to the final C-amidated nona-peptide, JAK inhibitor a step that is vitamin C dependent (Luck and Jungclas, 1987). As a result, release at the nerve endings includes the hormones, the carrier proteins, and residual bits of precursor. Under normal conditions, the release of the final nona-peptide involves a calcium-dependent fusion of the granules with the nerve terminal (Brownstein et al., 1980). Some mutations (such as P7L AVP) lead to dominant prohormones that are not secreted and accumulate in the endoplasmatic reticulum forming disulfide-linked oligomers that escape degradation, gradually aggregate to fibrillar proteins that cause cell death as in other neurodegenerative diseases (Birk et al., 2009). Prohormones may constitute up to 40% of total OT before

birth and have shown increased ratios in 4- to 6-year-old autistic children (Green et al., 2001). Classical neurotransmitters are packaged in Digestive enzyme small synaptic vesicles that are preferentially localized at synapses. Peptides are stored in large dense-core vesicles (LDCV) which tend to be distributed in soma, in dendrites, and in axonal varicosities as well as at nerve endings. Though both can be released by Ca2+-dependent exocytosis, exocytosis of synaptic vesicles requires a rise of intracellular [Ca2+] in the proximity of presynaptic Ca2+ channels, whereas peptide release is triggered by smaller but broader increases in intracellular [Ca2+]. Such changes in intracellular calcium could be brought about by high-frequency stimulation.