Progressive motoneuronopathy (PMN) is an autosomal recessive mouse disease, which is characterized by the development of hind limbs paralysis rapidly progressing to the anterior parts of the body, muscular atrophy, respiratory depression, and death at 6-7 postnatal weeks. Here, we recorded the resting membrane potential (RMP), spontaneous miniature endplate potentials (MEPPs), and quantum content of endplate potentials (EPP) at the diaphragm muscle fibers in controls and PMN mice aged 18 to 43 days. In control animals, there ws a progressive increase in RMP, MEEP frequency and EPP quantum content, as well as a decrease in mean MEPP amplitude. In PMN mice, the developmental increase in frequency and decrease in the amplitude of MEPPs was practically stopped at the postnatal day 18, whereas RMP increased but only until the age of 31 days and then progressively decreased. The distribution histogram of RMP in PMN mice older than 35 days revealed the existence of two subpopulations of muscle fibers: one showing a denervation-like decrease in RMP and the second, which was matching controls. In addition, EPP quantum content was significantly attenuated in older PMN animals. These results indicate that neurotransmission is severely affected in advanced, but not in early stage of disease, which is apparently due to a partial denervation of the muscles.
Neonatal pituitary cells express MT1 and MT2 subtype of melatonin receptors that are coupled to pertussis toxin-sensitive G proteins. Their activation by melatonin leads to a decrease in cAMP production and activity of protein kinase A, and attenuation of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion. Single cell calcium and electrophysiological recordings have revealed that a reduction in gonadotropin release results from melatonin-induced inhibition of GnRH-stimulated calcium signaling. Melatonin inhibits both calcium influx through voltage-dependent calcium channels and calcium mobilization from intracellular stores. Inhibition of calcium influx, probably in a cAMP/protein kinase C-dependent manner, and the accompanying calcium-induced calcium release from ryanodine-sensitive intracellular pools by melatonin results in a delay of GnRH-induced calcium signaling. Melatonin-
induced attenuation of GnRH-induced and inositol (1,4,5)-trisphosphate-mediated calcium release from intracellular pools attenuates the amplitude of calcium signal. The potent inhibition of GnRH-induced calcium signaling and gonadotropin secretion by melatonin provides an effective mechanism to protect premature initiation of pubertal changes that are dependent on plasma gonadotropin levels. During the development, such tonic inhibitory effects of melatonin on GnRH action gradually decline due to a decrease in expression of functional melatonin receptors. In adult animals, melatonin does not have obvious direct effects on pituitary functions, whereas the connections between
melatonin release and hypothalamic functions, including GnRH release, are preserved, and are critically important in synchronizing the external photoperiods and reproductive functions through still not well characterized mechanisms.