Fundamentals of neurogastroenterology: basic science

The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs.     

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons： a modeling study

Aim： 3-Methyl-6-chloro-7,8-hydroxy-1-（3-methylphenyl）-2,3,4,5-tetrahydro-1H-3-benzazepine （SKF83959） have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation.
Methods： Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na^＋ channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability.
Results： SKF83959 （50 μmol/L） shifted the inactivation curve of Na^＋ current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 （examined with current injection at the soma） was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability （examined with current injection at the dendrite） was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency.
Conclusion： SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug’s anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.     

Antibody-mediated impairment and homeostatic plasticity of autonomic ganglionic synaptic transmission

Antibodies against ganglionic acetylcholine receptors (AChR) are implicated as the cause of autoimmune autonomic ganglionopathy (AAG). To characterize ganglionic neurotransmission in an animal model of AAG, evoked and spontaneous excitatory post-synaptic potentials (EPSP) were recorded from neurons in isolated mouse superior cervical ganglia (SCG). In vitro exposure of ganglia to IgG from AAG patients progressively inhibited synaptic transmission. After passive transfer of antibody to mice, evoked EPSP amplitude decreased, and some neurons showed no synaptic responses. EPSP amplitude recovered by day 7 despite persistence of ganglionic AChR antibody in the mouse serum. There was a more persistent (at least 14-day) reduction in miniature EPSP amplitude consistent with antibody-mediated reduction in post-synaptic AChR. Although the quantal size was reduced, a progressive increase in the frequency of spontaneous synaptic events occurred, suggesting a compensatory increase in presynaptic efficacy. The quantal size returned to baseline by 21 days while the frequency remained increased for at least four weeks. Ganglionic AChR antibodies cause an impairment of autonomic ganglionic synaptic transmission. Homeostatic plasticity in autonomic neurotransmission could help explain the spontaneous clinical recovery seen in some AAG patients and may also play an important role in regulating normal autonomic reflexes.     

Postsynaptic influences on the vestibular non-deiters nuclei from primary vestibular nerve

Summary Neurones in the descending, medial and superior vestibular nuclei of the cats were explored with intracellular microelectrodes. Cerebellar- and spinal-projecting neurones were identified by their antidromic invasion from the region of fastigial nuclei and from the second cervical segment, respectively, and the others by their location. The central actions of the primary vestibular impulses upon these non-Deiters vestibular nuclei neurones were investigated by using electric stimulation of the ipsilateral vestibular nerve. Many of these cells received excitatory postsynaptic potentials (EPSPs) monosynaptically, similar to those evoked in the ventral Deiters neurones, as described elsewhere, except that the unitary EPSPs are often larger. Some cells received only polysynaptic EPSPs or IPSPs and a few cells were not influenced at all.     

Vestibulo-ocular reflex from the posterior canal nerve to extraocular motoneurons in the cat

Summary In the anesthetized cat, the posterior canal nerve (PCN) was stimulated by electric pulses and synaptic responses were recorded intracellularly in the three antagonistic pairs of extraocular motoneurons. Pure reciprocal effects were obtained in the motoneurons innervating the antagonistic pair of ipsilateral oblique muscles and the antagonistic pair of contralateral vertical rectus muscles. These responses consisted of low threshold disynaptic excitatory postsynaptic potentials (EPSPs) in either the contralateral superior oblique (c-SO) (trochlear) or contralateral inferior rectus (c-IR) motoneurons and of disynaptic inhibitory postsynaptic potentials (IPSPs) in either the ipsilateral inferior oblique (i-IO) or ipsilateral superior rectus (i-SR) motoneurons. In addition, disynaptic IPSPs were also found in (i-SO) motoneurons. Mixtures of low threshold (dior trisynaptic) EPSPs and IPSPs were found in all other extraocular motoneurons except for the contralateral lateral rectus (c-LR) motoneurons. These results may afford a basis for the characteristic eye movements induced by vertical canal nerve stimulation.     

Kindling-like state occurring on periodic increases in the extracellular K+ concentration in field CA1 in rat hippocampal slices

Transient periodic increases in the extracellular K⁺ concentration (20 mM, 30 sec, 3–6 episodes) led to the appearance of a kindling-like state in local neuronal networks of field CA1 of rat hippocampal slices. A criterion for the appearance of this state was a reduction in the threshold for the generation of multiple population discharges and an increase in the total number of population spikes within discharges (epileptiform activity). This state correlated with potentiation of excitatory postsynaptic potentials (EPSP) (long-term increases in pyramidal neuron excitability), but not with potentiation of glutamatergic synaptic transmission in field CA1 of hippocampal slices. The role of the various Ca²⁺ channels in inducing and maintaining the kindling-like state in rat hippocampal sections, evoked by periodic increases in the extracellular K⁺ concentration, is discussed. Group for the Study of the Mechanisms of Synaptic Transmission, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142292, Moscow Oblast, Russia. Translated from Rossiiki Fiziologischeskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 8, pp. 14–23, August, 1997.     

Facilitation of hippocampal CA3 pyramidal cell firing by electrical fields generated antidromically

In experiments on rats under urethane anaesthesia--in which the fimbria and hippocampal commissure had been cut previously to eliminate orthodromic inputs--the negative antidromic population spike evoked in CA3 by fimbrial stimulation was measured inside and outside 73 neurons in the stratum pyramidale. Subtraction of the extracellular from the intracellular records showed that on the average 39.2% (S.E. 1.93) of the extracellular population spikes appeared as a positive, depolarizing transmembrane potential. Similar measurements in the dendritic zone of CA3, where the extracellular antidromic population spike is positive, revealed a smaller and hyperpolarizing transmembrane potential, whereas presumed neuroglia showed no consistent transmembrane potential in either direction. Further tests demonstrated clear facilitation of individual pyramidal cell firing, synchronous with the antidromic population spike. These observations are consistent with the possibility that, owing to the unusually close packing and regular alignment of the pyramidal neurons, electrical field interactions in CA3 tend to promote synchronized mass discharges.     

Electrophysiological evidence for presynaptic inhibition of acetylcholine release by 5-hydroxytryptamine in the enteric nervous system

Intracellular recordings were made in vitro from myenteric neurones of guinea-pig ileum. 5-hydroxytryptamine was applied to the preparation either by superfusion or by iontophoresis on to the somatic membrane of the impaled cells. 5-Hydroxytryptamine (50 nM-2 μM) depressed the amplitude of the cholinergic fast excitatory postsynaptic potential in every neurone to which it was applied (n = 58). 5-Hydroxytryptamine did not change the amplitude of depolarizations produced by iontophoretic application of acetylcholine which were of a similar time course to the excitatory postsynaptic potential. Lysergic acid diethylamide (1 μM) and methysergide (1–30 μM) mimicked and sometimes blocked the action of 5-hydroxytryptamine.The results indicate that the inhibition of the peristaltic reflex by 5-hydroxytryptamine may be due to a blockade of transmission within the myenteric plexus brought about by a presynaptic action.