Murine models of cerebral ischemia, development of a mouse model of global cerebral ischemia; response of GluR2 knockout mice in a model of permanent focal cerebral ischemia

grantor: University of Toronto'I. Development of a four-vessel occlusion model of murine global cerebral ischemia: Influence of strain, ischemic duration and reperfusion time'. Cerebral ischemia resulting from cardiac arrest leads to delayed selective neuronal death. A similar pathological outcome is observed in a variety of experimental animal models of global ischemia. However, a reproducible murine model of ischemia resulting in delayed selective neuronal death has yet to be established. Such a model could be applied to transgenic and knockout mice to further elucidate the roles of specific genes and their products in the underlying pathophysiology resulting from cerebral ischemia. ' Purpose'. To develop a model of global cerebral ischemia in the mouse. ' Hypothesis'. Mice subjected to global ischemia produced by a four-vessel occlusion ('4-VO') model will yield the delayed selective death of >90% of pyramidal neurons in the CA1 region of the hippocampus. 'II. Mice lacking GluR2 are NOT more susceptible to focal cerebral ischemia'. The massive influx of Ca2+ ions through neuronal glutamate receptors has been implicated in the pathophysiology of focal cerebral ischemia. AMPA receptor ion channels are composed of heteromeric combinations of four subunits (GluR1, 2, 3 & 4). The inclusion of GluR2 in its composition renders AMPA receptors Ca2+-impermeable. The GluR2 Hypothesis states that cerebral ischemia induces the selective loss of this subunit, and consequently, increases Ca2+-permeability through GluR2-less AMPA receptors. 'Purpose'. We have therefore tested the response of mice lacking this subunit in a model of permanent focal cerebral ischemia. 'Hypothesis'. GluR2(-/-) mutant mice will be more susceptible to ischemic injury resulting from the permanent occlusion of their middle cerebral artery. (Abstract shortened by UMI.)M.Sc