Examination of the effects of reduction of afterdischarge threshold independent of repeated seizures using a novel electrical stimulation paradigm

The current group of studies was designed to separately investigate the effects of reducing the afterdischarge threshold from the effects of repeated seizures. No previously employed animal model of epilepsy allowed for experimental reduction of seizure threshold without the confounding effects of repeated seizure activity. Chapter 2 of this document described a novel protocol of sensorimotor neocortex stimulation that can be used to generate 4 experimental groups that show (1) Reduction of afterdischarge threshold and no seizures, (2) reduction of afterdischarge threshold and repeated seizures, (3) No change in afterdischarge threshold and repeated seizures, (4) No change in afterdischarge threshold and no seizures (control). This stimulation protocol was then used to examine these groups of rats on several post-stimulation measures to determine the effects of stimulation on multiple levels of analysis. Chapter 3 examined post stimulation alterations in gross motor activity and skilled forelimb use on the cylinder, rung walking, and single pellet reaching tasks. It was discovered that skilled reaching is disrupted by stimulation that results in seizure activity but no change in afterdischarge threshold. Chapter 4 examined the expression of the highly ordered topographically organized movement representations located in the sensorimotor neocortex following stimulation. It was discovered that stimulation that leads to repeated seizures but no change in afterdischarge threshold caused significant alterations in the total size of motor maps. Chapter 5 was an examination of the gross anatomical morphology of the dendrites of pyramidal cells located in layer III of sensorimotor neocortex. Chronic electrode implantation resulted in an overall reduction in dendritic length and branching in the right hemisphere containing a recording electrode. Within the right hemisphere, stimulation that resulted in repeated seizures but no reduction of afterdischarge threshold showed the greatest dendritic length, suggesting that repeated seizures had a protective effect against the damage of electrode implantation. Finally, Chapter 6 was an ultrastructural analysis of the density of synapses in layer V of the sensorimotor neocortex. It was discovered that stimulation that reduced threshold with no seizures, and stimulation that caused no change in threshold with repeated seizures both lead to an increase in the highly efficacious perforated synaptic subtype. Furthermore, stimulation that caused both reduction of afterdischarge threshold and repeated seizures resulted in a decrease of perforated synapses, suggesting a non-linear relationship between these two effects. The current results highlight the necessity of examining all aspects of the administration of electrical stimulation, and suggest that previous models of epilepsy that claim seizure-induced changes may actually be observing a contribution of the underlying effects of reducing the seizure threshold.