Time course of development of supersensitivity to topical acetylcholine in partially isolated cortex

Abstract

In alert monkeys the time course for development of supersensitivity to topical acetylcholine in partially isolated frontal cerebral cortex was determined. Thresholds for paroxysmal discharge fell progressively and markedly during 3 weeks, further in 5 and somewhat more after 6 months. ACh supersensitivity was demonstrated in chronic “isolated” occipital cortex. Epileptiform discharges were recorded selectively from chronic partially isolated frontal cortex on peripheral nerve stimulation and these spread, causing a clinical convulsive seizure when the open end of the isolation extended into the precentral gyrus. The basic mechanisms responsible for the supersensitivity are unknown but evidence presented and much in the pertinent literature is in keeping with the hypothesis that partial isolation of cortical cells, i.e., denervation, deafferentation, or disuse may be important. It is suggested that peripheral nerve stimulation, like arousal, may cause an outflow of ACh on the normal brain surface and over the open end of a partially isolated area, which, especially, in the presence of a diminished cholinesterase activity (in partially isolated cortex), could act like topical ACh, cause a DC shift and an epileptiform discharge. Kristiansen and Courtois (1949) and Burns (1950) have provided a technique whereby cerebral cortex may be partially or completely neuronally isolated and have described the electrical changes in their acute preparations both spontaneous and after stimulation electrically or with acetylcholine. Henry (1949), Henry and Scoville (1952), and Echlin et al. (1950, 1952) have reported spontaneous periodic electrical “bursting” from acutely and chronically “isolated” human and animal cerebral cortex. It has also been shown that the paroxysmal discharges which may be precipitated from partially isolated cerebral cortex by electrical stimulation usually become, with time, more prolonged (Obrador 1947; Echlin and McDonald 1954; Grafstein and Sastry 1957; Echlin 1959; Sharpless and Halpern 1962; Sharpless 1969) and that in chronic partially isolated monkey or human, frontal or parietal cortex (sectioned subpially along 3 sides and undercut), paroxysmal epileptiform discharges can be consistently precipitated with much weaker concentrations of topical acetylcholine (and certain other excitatory agents) than in normal or acutely isolated cortex (Echlin and McDonald 1954; Echlin 1959; Echlin and Battista 1963) providing especially that the ACh solutions are applied intermittently (see below). It was suggested (Echlin and McDonald 1954; Echlin 1959) that the increased excitability in chronic “isolated” preparations might be a manifestation of denervation supersensitivity as expressed in Cannon's Law of Denervation (1939). Drake and Stavraky (1948), Loesser and Ward (1967), Stavraky (1961) and Ward (1969) have presented a mass of evidence that an increase in sensitivity to a variety of stimulating agents occurs following partial isolation (denervation or deafferentation) of neurons in the central nervous system. Krnjević et al. (1970) when recording unit responses to microiontophoretic application of ACh or of l-glutamate, found no evidence that prolonged isolation of cortex caused an increase in neuronal sensitivity to these substances and, interestingly, during paroxysmal activity precipitated by surface electrical stimulation, there was an absence of unit discharges. It was concluded that these findings provided no support to the theory that the supersensitivity of long-isolated slabs could be ascribed to denervation supersensitivity. Spehlmann (1971) and Spehlmann et al. (1971) using both macro- and microelectrode recording found no evidence of a supersensitivity to continuous topical application of ACh in chronic isolated cat occipital cortex and concluded that ACh (endogenous) does not participate in the elaboration of the epileptiform activity in these preparations. They did, however, find a prolongation of the discharge to topical ACh and to electrical stimulation. The present study is concerned with: (I) Plotting the time course of development of supersensitivity to topical acetylcholine in partially isolated frontal cortex in alert monkeys. (II) Determining whether or not monkey occipital cortex becomes supersensitive to topical ACh following chronic partial isolation. (III) Illustrating that prolonged peripheral nerve stimulation caused epileptiform discharges selectively from partially isolated frontal cortex which spread and produced clinical seizures when the open end of the isolation extended into the precentral gyrus. (Preliminary report without illustrations, Echlin and Battista 1961.)