The molecular, cellular and behavioural effects of electroconvulsive stimulation in the rodent brain
Citation:
Sinéad O'Donovan, 'The molecular, cellular and behavioural effects of electroconvulsive stimulation in the rodent brain', [thesis], Trinity College (Dublin, Ireland). Institute of Neuroscience, 2012, pp 482Download Item:
Abstract:
Electroconvulsive therapy (ECT) is the most effective treatment available for severe depression however its mechanisms of action have not been fully established. ECT administration is associated with memory deficits. To maintain the antidepressant efficacy of ECT while reducing its associated side effects, the parameters by which ECT is administered have been adjusted. Recently, it has been proposed that reducing stimulus pulse width from brief pulse (0.5 ms) to ultra brief (0.3 ms) pulse may maintain the treatment effect of ECT but reduce the side effects. Electroconvulsive stimulation (ECS) is the animal model of ECT. Animals were administered a chronic course of either brief pulse, ultra brief pulse or sham ECS, consisting of ten treatments. The cellular, molecular and behavioural effects of the different pulse widths were compared. Brief pulse but not ultra brief pulse ECS induced a significant increase in cell proliferation in the dentate gyrus. Brief pulse ECS treatment resulted in a significant increase in brain derived neurotrophic factor (BDNF) expression in the hippocampus but not the frontal cortex. Ultra brief pulse ECS did not significantly affect BDNF expression in either brain region. Behaviourally, brief pulse ECS treatment induced an effective antidepressant response in the forced swim test by significantly reducing animal immobility time. This result was not obtained in ultra brief pulse treated animals. In summary, brief pulse ECS is more effective at inducing the cellular, molecular and behavioural effects associated with antidepressant treatment than ultra brief pulse ECS. Further study will be required to fully determine whether ultra brief pulse ECS offers an improvement over the side effects associated with ECS treatment. Proteins are cellular workhorses and control many of the functions carried out in the cell (Strong and Eisenberg, 2007). ECS models an effective antidepressant treatment but the proteomic changes it induces in the hippocampus and frontal cortex have yet to be studied. Therefore, animals were treated with an acute, chronic or chronic + 4 week course of ECS and samples for 2-dimensional Difference in Gel Electrophoresis (2D-DiGE) were collected. The samples were fluorescently labelled and separated in two dimensions according to their isoelectric point and molecular weight. This resulted in the resolution of over 1,000 protein spots in each study. Univariate and multivariate data analysis techniques were employed to determine which protein spots were differentially regulated following treatment with ECS. Protein spots with a p-value ≤0.05 were short-listed for selection and identification. Preparative 2D gels were run and, unlike DiGE, the gels were post-stained. The short-listed proteins were picked from the preparative gels. Due to technical differences between gels, a limited number of significantly differentially expressed protein spots were picked. The selected spots were trypsin digested and identified by Linear Trap Quadrupole-Orbitrap mass spectrometry. This process was conducted for tissue samples collected from the hippocampus and the frontal cortex. Mass spectrometry identified multiple proteins with several different proteins identified in each proteins spot. In order to organise and categorise the identified proteins, gene ontology (GO) analysis and pathway analysis [for example the Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Ingenuity Pathway Analysis (IPA)] were conducted for each study. This highlighted the expression of cytoskeletal-related proteins, in particular, following ECS administration in both the hippocampus and frontal cortex. A number of cytoskeletal-related proteins were selected for further confirmation by semi-quantitative immunoblotting. Actin was statistically differentially expressed following ECS while trends in expression were found between control and ECS samples for other cytoskeletal proteins. ECS treatment induced a range of subtle changes in cytoskeletal protein expression that may be involved in its mechanisms of action. Future work analysing the proteins identified following ECS treatment will help to elucidate the effects of ECS and potentially of ECT on the brain.
Author: O'Donovan, Sinéad
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Doctor of Philosophy (Ph.D.)Publisher:
Trinity College (Dublin, Ireland). Institute of NeuroscienceNote:
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Psychiatry, Ph.D., Ph.D. Trinity College DublinMetadata
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