Epileptiform Activity in Isolated Cortex and Hippocampal Preparations, and Its Modulation by Purinergic Compounds

Chesi, Alexander (1995) Epileptiform Activity in Isolated Cortex and Hippocampal Preparations, and Its Modulation by Purinergic Compounds. PhD thesis, University of Glasgow.

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1. This dissertation addresses both the physical requirements (in terms of the minimal mass of tissue needed) for the generation and propagation of epileptiform activity, and the purinergic modulation of this epileptiform activity in the cerebral cortex. Studies on the minimal mass were performed in rat somatosensory cortex in vivo, using subpial transsections based on a recently developed neurosurgical approach to the treatment of drug-resistant epilepsy (Morrell et al 1989: "Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy"), in conjunction with the iontophoretic application of the convulsant penicillin. For a detailed analysis of the structural requirements for epileptiform activity and the rapid application and wash-out of drugs of known concentration, a novel in vitro model of the isolated neocortical column was developed which allowed the manipulation of radial intracortical pathways via pressure ejection of drugs at various cortical depths, and the isolation of specific layers by subsectioning the tissue. It therefore provided a unique way of studying the intrinsic pathways of individual cortical layers. The epileptiform potentials in rat and mouse neocortical cylinders were recorded with standard extracellular recording techniques in an attempt to elucidate some of the aspects of the ongoing debate on whether the so-called 'cortical columns' are hardwired information processing units, or functional groups of co-active neurones whose configuration varies with the task performed. 2. After preliminary findings in rat neocortex in vivo had indicated that the minimal mass, i.e. the smallest block of cortical brain tissue able to generate epileptiform spiking, was small enough to be investigated in vitro, work on the subsequently developed in vitro model of the cortical column clearly showed that the minimal diameter was below that of the postulated columns defined by the so-called 'barrel' structures found in layer IV of the rat somatosensory cortex. Furthermore, blocks of brain tissue (containing an estimated 1500 neurones) which excluded layer IV displayed epileptiform activity which was indistinguishable from that observed in preparations containing all neocortical layers, or indeed from records obtained by other groups in chronically isolated neocortex in situ. It is concluded that the minimal mass problem is, to a certain extent, merely a question of the degree of connectivity; from the results of the present study, no horizontal boundaries corresponding to the postulated 'cortical modules' were found to exist with respect to the generation of paroxysmal discharges. Similarly, the importance of layer IV in the generation of epileptiform discharges appears to pertain only to the specialised case of discharges induced by GABA receptor blockade, as exclusion of this layer did not affect the ability of the tissue to display the spikes/afterdischarges commonly observed in intact cortical slices in vitro, and in cortical subpial isolations in vivo. 3. In Part Two, the purinergic modulation of this epileptiform activity was studied in mouse neocortical cylinders and in rat hippocampal slices. The inhibitory effects of adenosine (a metabolite of nucleotide hydrolysis which may act as an 'endogenous anticonvulsant') on low-magnesium ACSF-induced epileptiform activity are described, followed by an analysis of the factors contributing to the proconvulsant effects caused by selective adenosine A1 receptor blockade in vitro. The main compound used was l,3-dipropyl-8-cyclopentyl-xanthine (DPCPX), a highly selective A1 antagonist which in previous in vitro studies had been reported to induce persistent epileptiform activity by an unknown mechanism after transient application; these prolonged epileptogenic effects are not usually observed after the application of less selective adenosine antagonists. 4. Despite the marked proconvulsant effects reported for DPCPX in vitro, the drug does not induce seizures when administered in vivo. A similar effect was observed in the present study in vitro', on the basis of these findings, it is suggested that the main physiological role of adenosine in the brain is to exert an activity-dependent negative feedback control which limits the effects of calcium influx through voltage-activated Ca++ channels, rather than the 'inhibitory purinergic tone' proposed by some authors.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Oliver Holmes
Keywords: Neurosciences, Pathology
Date of Award: 1995
Depositing User: Enlighten Team
Unique ID: glathesis:1995-75696
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:55
Last Modified: 19 Nov 2019 18:55
URI: https://theses.gla.ac.uk/id/eprint/75696

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