This thesis focusses on the seizure-promoting effects of second messengers, in particular calcium and others activated by calcium in CA1 subfield of rat hippocampus in situ and in vitro. Interictal discharges were simulated in hippocampal slices using the low Ca$ sp{2+}$ model where synaptic transmission is blocked. The antiepileptic drug valproic acid (VPA), which is postulated to potentiate GABAergic responses, reduced the low Ca$ sp{2+}$ field bursts, thereby suggesting a non-synaptic mechanism of action of VPA. Extracellular and intracellular recordings from hippocampal neurones bathed in low Ca$ sp{2+}$ solution revealed that even though evoked transmitter release was blocked, small spontaneous GABAergic release still persisted and that a voltage-dependent Cl conductance contributed to burst termination. To test the hypothesis that epileptiform activity induced by lowering extracellular Ca$ sp{2+}$ was in part due to an alteration in the delicate balance between intracellular messengers, I investigated the effects of Ca$ sp{2+}$ (a) on the activity of hippocampal neurones, and (b) on the second messengers activated by acetylcholine (ACh), a neuromodulator known for its seizure promoting effects. Inhibiting cyclic nucleotide-dependent kinase activity was H-8 did not have any effect either on excitability of CA1 neurones or the excitatory actions of ACh. Activation of protein kinase C (PKC), a Ca$ sp{2+}$-binding protein, by phorbol esters enhanced high threshold Ca$ sp{2+}$ currents and subsequently facilitated neurotransmitter release (both excitatory and inhibitory) without significantly affecting ACh-induced effects. Inhibition of PKC by several dual PKC and Ca$ sp{2+}$/calmodulin-dependent kinase antagonists, such as H-7, sphingosine, and trifluoroperazine reduced inhibitory transmission and prevented ACh-induced effects. / The evidence presented in this thesis was combined with that in the literature to propose a model accounting for the seizure-promoting effects of ACh: that gangliosides and/or sphingolipids are metabolized to sphingosine upon muscarinic receptor activation leading to inhibition of both PKC and Ca$ sp{2+}$/calmodulin-dependent kinases.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74618 |
| Date | January 1990 |
| Creators | Agopyan, Nadia M. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001214705, proquestno: AAINN67649, Theses scanned by UMI/ProQuest. |
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