The present review examines the experimental evidence supporting the existence of central mechanisms able to modulate the synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates. The first section covers work on the mode of operation and the synaptic mechanisms of presynaptic inhibition, in particular of the presynaptic control involving axo-axonic synapses made by GABAergic interneurons with the terminal arborizations of the afferent fibers. This includes reviewing of the ionic mechanisms involved in the generation of primary afferent depolarization (PAD) by GABAergic synapses, the ultrastructural basis underlying the generation of PAD, the relationship between PAD and presynaptic inhibition, the conduction of action potentials in the terminal arborizations of the afferent fibers, and the modeling of the presynaptic inhibitory synapse. The second section of the review deals with the functional organization of presynaptic inhibition. This includes the segmental and descending presynaptic control of the synaptic effectiveness of group-I and group-II muscle afferents, the evidence dealing with the local character of PAD as well as the differential inhibition of PAD in selected collaterals of individual muscle-spindle afferents by cutaneous and descending inputs. This section also examines observations on the presynaptic modulation of large cutaneous afferents, including the modulation of the synaptic effectiveness of thin myelinated and unmyelinated cutaneous fibers and of visceral afferents, as well as the presynaptic control of the synaptic actions of interneurons and descending tract neurons. The third section deals with the changes in PAD occurring during sleep and fictive locomotion in higher vertebrates and with the changes of presynaptic inhibition in humans during the execution of a variety of voluntary movements. In the final section, we examine the non-synaptic presynaptic modulation of transmitter release, including the possibility that the intraspinal endings of primary afferents also release colocalized peptides in a similar way as in the periphery. The outcome of the studies presently reviewed is that intraspinal terminals of sensory fibers are not hard-wired conductors of the information generated in their peripheral sensory receptors, but dynamic systems that convey information that can be selectively addressed by central mechanisms to specific neuronal targets. This central control of information flow in peripheral afferents appears to play an important role in the generation of integrated movements and processing of sensory information, including nociceptive information.

Presynaptic inhibition in the vertebrate spinal cord revisited.

Measurement of Ca2+ concentrations in living cells

Extracellular calcium and potassium activities (aCa and aK) as well as neuronal activity were simultaneously recorded with ion-sensitive electrodes in the somatosensory cortex of cats. Baseline aCa was 1.2–1.5 mM/1, baseline a
 k
 2.7–3.2 mM/1. Transient decreases in aCa and simultaneous increases in aK were evoked by repetitive stimulation of the contralateral forepaw, the nucleus ventroposterolateralis thalami and the cortical surface. Considerable decreases in aCa (by up to 0.7 mM/1) were found during seizure activity. A fall in aCa preceded the onset of paroxysmal discharges and the rise in aK after injection of pentylene tetrazol. The decrease in aCa led also the rise in aK during cyclical spike driving in a penicillin focus. It is concluded that alterations of Ca++ dependent mechanisms participate in the generation of epileptic activity.

Extracellular free calcium and potassium during paroxsmal activity in the cerebral cortex of the cat.

1 Neurotransmitter-receptors in the membrane of Xenopus oocytes have been studied using electrophysiological techniques Neurotransmitters and related agents were applied while recording either membrane potential or membrane current The majority of ovarian oocytes used were at stages IV and V

2 Three types of oocytes were examined: inner ovarian epithelium covered (ec) oocytes; epithelium manually removed (er) oocytes; and collagenase treated (ct) ooctyes

3 Ovarian oocytes are sensitive to some cholinergic and catecholaminergic agents Responses to serotonin were seldom observed and when present were much weaker than responses to other agents No responses were observed to the amino acids: aspartate, glutamate, γ-aminobutyric acid, and glycine; or to octopamine and histamine

4 Acetylcholine (ACh) usually depolarized the membrane, in a dose-dependent manner, with threshold concentrations as low as 10-9 m The ACh-potential was due to an increase in Cl permeability and had a reversal potential around — 19 mV The intracellular Cl ion activity, measured with a Cl-ion sensitive micro-electrode, was about 65 mm and the estimated Cl-ion equilibrium potential, ECl, agreed with the reversal potential of the ACh-potential

5 Curare (10-4 m), tetrodotoxin (10-6 m), or α-bungarotoxin (10-6 g/ml) did not block the response to 10-6 m-ACh; whereas atropine (10-7 m) blocked it No response to nicotinic agents (eg nicotine, 1,1-dimethyl-4-phenylpiperazinium) was observed These results suggest that the ACh receptors in the oocyte membrane are muscarinic in nature

6 The apparent latency of the ACh potential, examined by ionophoretic application of ACh to er oocytes and ct oocytes, ranged from 0·5 sec to over 20 sec Intracellular injection of ACh was without effect

7 Responses to catecholamines were observed mostly in ec oocytes; while in er and ct oocytes they were rare and of very small amplitudes

8 The usual response to both dopamine and (—)-epinephrine was a transient hyperpolarization manifested by an initial increase in K-permeability followed by a decrease The latency of these responses ranged from 10 sec to over 30 sec and their reversal potential was nearly — 100 mV, which coincided with EK

9 Oocytes responded to the β-adrenergic receptor agonist, isoproterenol, as well as (—)-epinephrine Pre-treatment with the β-adrenergic receptor blocker, propranolol, abolished the response to both (—)-epinephrine and (—)-isoproterenol The dopamine potential was also reduced considerably Both the α-adrenergic receptor agonist, phenylephrine, and the α-adrenergic receptor blocker, phentolamine, were without effect

10 Maturation of the oocytes, induced in vivo by gonadotropin or in vitro by progesterone, led to loss of responsiveness to both cholinergic and catecholaminergic agents

Cholinergic and catecholaminergic receptors in the Xenopus oocyte membrane.

Potassium, calcium, and magnesium are three inorganic ions that occur in significant quantity in extracellular fluid of the mammalian brain and have powerful effects on the functioning of nervous tissue. In different ways all three influence the excitability of neurons and the release of transmitters from presynaptic terminals. Two different points of view have evolved concerning the regulation of these ions in the central nervous system (CNS). Some authors have emphasized the narrow range of the activity of these ions in the healthy brain and have concluded that stability of brain function requires stability of the extracellular activity of these ions. Others have argued that in the course of evolution the mammalian brain must have found an advantageous use for these powerful agents in the normal regula­ tion of neuronal excitability. According to this view, programmed varia­ tions in [K+]o, [Ca2+]o, and perhaps also [Mg2+]o may be an integral component in the normal function of the central nervous system. Due to the recent development of potassium-selective microelectrodes (184) there has been a new surge of interest in the functional significance of potassium distribution in the nervous system. This selective review may be supplemented by consulting more general reviews on brain electrolytes (69, 72, 74, 83, 90, 158, 175).

Jr. John Lawrence Walker

Papers

Ion Specific Liquid Ion Exchanger Microelectrodes