Year: 2015
Type: dissertation
Abstract: General anesthetics are widely used to allow patients to tolerate surgery and to sedate patients in intensive care units. Anesthesia causes long-term memory deficits in laboratory animals, suggesting it could contribute to memory loss in patients. However, the mechanisms underlying postanesthetic memory deficits are unknown. Most anesthetics cause neurodepression by allosterically increasing the activity of gamma-aminobutyric acid type A (GABA-A) receptors. In particular, positive allosteric modulation of alpha5 subunit-containing GABA-A (alpha5GABA-A) receptors contributes to the acute, amnestic effects of the anesthetic etomidate. Once the anesthetic has been eliminated, allosteric modulation of GABA-A receptors is rapidly reversed and it is assumed that GABA-A receptors do not contribute to memory deficits that persist after anesthesia. However, previous work from our lab suggests that alpha5GABA-A receptors may play a role in postanesthetic memory loss, as treatment with a drug that inhibits these receptors before anesthesia prevents memory deficits. I hypothesized that exposure to anesthetics results in a sustained increase in alpha5GABA-A receptor activity, which causes memory deficits. First, my data showed that alpha5GABA-A receptors are required for postanesthetic memory deficits as wild-type, but not Gabra5 null-mutant mice (Gabra5-/-), exhibit impaired memory performance on the object recognition memory task. These deficits are evident for 24 hours after isoflurane anesthesia and persist for up to 1 week after exposure to the injectable anesthetic etomidate. The mechanism underlying these memory deficits is likely a sustained increase in the function of alpha5GABA-A receptors as a single, in vivo exposure to the anesthetic etomidate (8 mg/kg i.p.) or isoflurane (1.3%, 1 h) increases a tonic inhibitory current that is mediated by alpha5GABAA receptors and increases cell-surface expression of alpha5GABA-A receptors for least 1 week with full recovery by 2 weeks. Memory deficits in wild-type mice are reversed after anesthesia by inhibiting alpha5GABA-A receptor activity with the inverse agonist L-655,708. Collectively, these results refute the widely-held belief that the function of GABA-A receptors returns to baseline after the anesthetic agent has been eliminated. Furthermore, the data present a mechanism and a plausible treatment strategy for postanesthetic memory deficits.
Source: TSpace (University of Toronto)
Author: Agnieszka A. Zurek
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2760098090