Functional Implications of Neurotransmitter Segregation

Here, we present and discuss the characteristics and properties of neurotransmitter segregation, a subtype of neurotransmitter cotransmission. We review early evidence of segregation and discuss its properties, such as plasticity, while placing special emphasis on its probable functional implications, either in the central nervous system (CNS) or the autonomic nervous system. Neurotransmitter segregation is a process by which neurons separately route transmitters to independent and distant or to neighboring neuronal processes; it is a plastic phenomenon that changes according to synaptic transmission requirements and is regulated by target-derived signals. Distant neurotransmitter segregation in the CNS has been shown to be related to an autocrine/paracrine function of some neurotransmitters. In retinal amacrine cells, segregation of acetylcholine (ACh) and GABA, and glycine and glutamate to neighboring terminals has been related to the regulation of the firing rate of direction-selective ganglion cells. In the rat superior cervical ganglion, segregation of ACh and GABA to neighboring varicosities shows a heterogeneous regional distribution, which is correlated to a similar regional distribution in transmission strength. We propose that greater segregation of ACh and GABA produces less GABAergic inhibition, strengthening ganglionic transmission. Segregation of ACh and GABA varies in different physiopathological conditions; specifically, segregation increases in acute sympathetic hyperactivity that occurs in cold stress, does not vary in chronic hyperactivity that occurs in hypertension, and rises in early ages of normotensive and hypertensive rats. Given this, we propose that variations in the extent of transmitter segregation may contribute to the alteration of neural activity that occurs in some physiopathological conditions and with age.

Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia

Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14–16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity.

Reactive oxygen species alters the electrophysiological properties and raises [Ca2+]i in intracardiac ganglion neurons

We have investigated the effects of the reactive oxygen species (ROS) donors hydrogen peroxide (H2O2) and tert-butyl hydroperoxide ( t-BHP) on the intrinsic electrophysiological characteristics: ganglionic transmission and resting [Ca2+]i in neonate and adult rat intracardiac ganglion (ICG) neurons. Intracellular recordings were made using sharp microelectrodes filled with either 0.5 M KCl or Oregon Green 488 BAPTA-1, allowing recording of electrical properties and measurement of [Ca2+]i. H2O2 and t-BHP both hyperpolarized the resting membrane potential and reduced membrane resistance. In adult ICG neurons, the hyperpolarizing action of H2O2 was reversed fully by Ba2+ and partially by tetraethylammonium, muscarine, and linopirdine. H2O2 and t-BHP reduced the action potential afterhyperpolarization (AHP) amplitude but had no impact on either overshoot or AHP duration. ROS donors evoked an increase in discharge adaptation to long depolarizing current pulses. H2O2 blocked ganglionic transmission in most ICG neurons but did not alter nicotine-evoked depolarizations. By contrast, t-BHP had no significant action on ganglionic transmission. H2O2 and t-BHP increased resting intracellular Ca2+ levels to 1.6 ( ± 0.6, n = 11, P < 0.01) and 1.6 ( ± 0.3, n = 8, P < 0.001), respectively, of control value (1.0, ∼60 nM). The ROS scavenger catalase prevented the actions of H2O2, and this protection extended beyond the period of application. Superoxide dismutase partially shielded against the action of H2O2, but this was limited to the period of application. These data demonstrate that ROS decreases the excitability and ganglionic transmission of ICG neurons, attenuating parasympathetic control of the heart.