Postpartum C57BL/6 Mice Display Impaired Mitochondrial Function, Decision Making, and Cerebral Perfusion following Exposure to Preeclampsia/Eclampsia-like Conditions

Mitochondria, the key regulators of cellular health and signaling, have been linked to the pathophysiology of preeclampsia and eclampsia (PE/E), with dysfunctional mitochondria reported in the placenta and kidneys. Additionally, dysfunctional mitochondria are linked to aging and dementia and women with a history of PE/E have an increased risk of developing vascular dementia. The mechanisms linking PE/E to vascular dementia are not fully known. We hypothesized that dysfunctional cerebral mitochondria and hypoperfusion of the prefrontal cortex may link PE/E-like pregnancy history to postpartum dementia-like characteristics. To test this, pregnant C57BL/6J mice underwent sham or RUPP surgeries at gestational day (GD) 13.5 followed by injection with pentylenetetrazol (PTZ, 40mg/kg, i.p), a seizure inducing GABA receptor antagonist, at GD 18.5 to mimic PE/E conditions. Mice delivered naturally and at 2 months postpartum, spatial learning and executive decision making were measured using the Barnes maze. Perfusion of the prefrontal cortex was measured using Laser Speckle Imaging. Mitochondrial respiratory chain function and aconitase activity in frozen prefrontal cortex were measured using Spectrophotometry and the Oroboros O2k FluoRespirometer. Mice exposed to RUPP+PTZ showed modest learning impairments, taking the longest time to navigate to the escape box on day 1 of training compared to Sham-PTZ (p=0.014). RUPP+PTZ mice utilized a direct search strategy 17% of the time on Day 1 (p<0.05) compared to 55% in Sham-PTZ. There was a significant decrease in prefrontal cortex perfusion in RUPP+PTZ exposed mice compared to both RUPP-PTZ (p=0.001) and Sham+PTZ animals (p=0.016). Miceexposed to PTZ also had altered respiratory complex I, III, and IV activity with animals exposed to Sham+PTZ having a significant increase in NADH oxidation compared to Sham-PTZ (p=0.047) and RUPP+PTZ (p=0.012). Cytochrome C reduction and oxygen consumption rates were also significantly higher in RUPP+PTZ animals compared to Sham+PTZ (p=0.028 and p=0.045 respectively). There was no difference in aconitase activity, although in Sham+PTZ mice, there was a positive correlation between aconitase activity and Complex III (r=0.920, p=0.027) and Complex I and Complex IV (r=0.971, p=0.006). Together, these results demonstrate that PE/E-like conditions result in cerebral mitochondrial dysfunction, hypoperfusion of the prefrontal cortex, along with modest impaired spatial navigation on the Barnes maze at 2 months postpartum. Ongoing studies will assess changes in mitochondrial morphology in different brain regions and changes in vascular-specific mitochondrial function and morphology at different postpartum time-points. Funding Source: T32 HL105324 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.