LELAND STANFORD JUNIOR UNIVERSITY, THE
In this grant, we aim to understand the contribution of astrocytes to ischemic brain injury in the hippocampus. One of the most feared disabilities in survivors of cardiac arrest is neurological impairment. Global cerebral ischemia, as seen with adult cardiac arrest, causes delayed loss of CA1 pyramidal neurons in the hippocampus while the nearby dentate gyrus (DG) is relatively resistant. Despite much work on hippocampal neuronal injury, little is known of the effects of ischemia on hippocampal astrocytes in these two
regions. Our funded proposal encompasses three aspects of hippocampal astrocyte survival and response to ischemia and ischemia-like stress. We would like to hire a new researcher to speed up work on this project. As a direct result of our work to date, we have made two novel and significant observations that warrant follow up studies. First, we have found that the targeted expression of Hsp72 in astrocytes reduces oxidative stress and protects against loss of astrocytic glutamate transporter 1 (GLT1), suggesting that ROS accumulation in astrocytes is an early step in neuronal death after ischemia (Parent Aim 3). As we have previously published, the loss of GLT1 in CA1 astrocytes is closely correlated with loss of CA1 neurons. We will now directly test whether a mitochondrial-specific anti-oxidant (SOD2) is neuroprotective, to gather more
evidence for the importance of early impairment of astrocyte mitochondria. Second, we have found that using hippocampal slices from postnatal day 3-5 rather than postnatal day 8-12 results in a different pattern of ischemic neuronal hippocampal injury. We hypothesize that low levels of endogenous GLT1 expression at these early ages contributes to the altered pattern of injury.
With supplement support, we will further specific aims 1-3 of the parent grant by following up on the findings discussed above. Specifically, we will:
Compare mitochondrial-specific oxidant scavenging (using SOD2) to the more global effects of cytosolic Hsp72 overexpression.
Hypothesis 1: Targeted overexpression of Hsp72 or SOD2 in astrocytes reduces vulnerability of CA1 neurons via protection of the astrocyte mitochondria (relates to Aims 2 & 3)
Study the age-related changes in hippocampal ischemic vulnerability
Hypothesis 2: Age-related changes are due to the patterns of astrocyte maturation in CA1 and DG, specifically as maturation relates to mitochondrial function (Relates to Aims 1 & 2)