Date of Graduation
School of Medicine
Physiology, Pharmacology & Neuroscience
The cerebral cortex, which include the neocortex and hippocampus, is an elaborate neuronal network communicating mainly through glutamate and gamma-aminobutyric acid (GABA). Glutamate, operating via AMPA, kainate, and NMDA receptors excites neurons, and operating via metabotropic glutamate receptors can either increase or decrease the excitation in the neuronal network. GABA, operating through GABAA and GABAB receptors, inhibits the mature neuronal network, and GABAA receptor blockade in the adult cerebral cortex leads to epileptiform bursts. In contrast, in the neonatal cerebral cortex, GABAA has been proposed to function as an excitatory neurotransmitter, and glutamatergic synapses are claimed to be underdeveloped. It is important to understand the mechanisms underlying epileptiform activity in the neonate, because epileptiform activity in the neonate can potentially damage the developing cerebral cortex. In this dissertation I explore the role of GABA in controlling epileptiform activity in the neonatal cerebral cortex. Bath application of GABAA receptor antagonists induced spontaneous generation of large-amplitude population discharges resembling interictal bursts, a form of epileptiform activity; activation of GABAA receptors reduced the amplitude of interictal bursts. Interictal bursts were mediated by glutamatergic neurotransmission, demonstrating that glutamate synapses are functional in the neonate. We conclude that GABA is inhibitory in the neonatal cerebral cortex because it serves to suppress excitatory synchronous activity. Interictal bursts in the neonatal hippocampus were generated in a temporally precise rhythm. The rhythmicity of interictal bursts was not modulated by GABAB receptors, calcium activated potassium conductances, or internally released calcium, butmanipulations that facilitate or suppress the hyperpolarization-activated cation current, Ih, increased or decreased, respectively, the frequency of the bursts. We conclude Ih plays a major role in pacing neonatal interictal bursts. Immunocytochemistry illustrated that Ih channel subunits in neonatal pyramidal neurons were distributed predominately in somata, while in the juvenile and mature hippocampus and neocortex the subunits were mostly found in GABAergic terminals and in the membrane of apical dendrites of pyramidal neurons, with diminished or no expression inside the somata. We conclude that the unique expression of Ih channel subunits in the neonatal hippocampus could contribute to the increased temporal precision of interictal bursts at this developmental stage.
Wells, Jason Eric, "Epileptiform bursting in the disinhibited neonatal cerebral cortex" (2003). Graduate Theses, Dissertations, and Problem Reports. 1905.