Date of Award

4-19-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Van A. Doze

Abstract

Norepinephrine (NE) is an endogenous neurotransmitter distributed throughout the mammalian brain. NE has demonstrated proconvulsant and antiepileptic properties. In higher cortical structures such as the hippocampus, a region often involved in temporal lobe epilepsy, NE has been shown to reinforce the cognitive processes of attention and memory. However, the specific mechanism of these actions has not been clearly established. To address this, the effects of NE were studied on hippocampal CA3 network activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations suppressed the number of bursts, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of β AR blockade, increasing concentrations of NE elicited a monophasic decrease in burst frequency, while in α AR blockade, NE produced a monophasic increase in network activity. Concentration-response curves in the presence of antagonists selective for α1 or α2 ARs were then used to determine which α AR type was involved. Results suggested that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 network activity are mediated primarily via β1 and α2 ARs, respectively. Utilizing single-cell RT-PCR, concentration-response curves of AR agonists and Schild regressions of subtype-selective antagonists, a β1 AR mediated enhancement and a α2A AR mediated inhibition of hippocampal CA3 network activity was identified. Pharmacological and surgical isolation localized these effects to the CA3 pyramidal cells themselves. I hypothesized that α2A AR activation inhibits network activity by disrupting glutamate release at CA3-CA3 pyramidal cell recurrent synapses. Using whole-cell recordings in rat hippocampal slices, excitatory post-synaptic currents evoked from the major connections of the CA3 pyramidal neurons were examined to further localize this adrenergic effect. Evidence suggested that α 2 AR stimulation inhibits only recurrent CA3 synapses, while the excitatory drive to and from these cells remains unchanged. Since this α2 AR response is specific to CA3 recurrent synapses, this may explain how the adrenergic system may be antiepileptic while at the same time not diminishing other areas of cognitive function such as learning or memory.

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