Increased hippocampal cannabinoid 1 receptor expression is associated with protection from severe seizures in pregnant mice with reduced uterine perfusion pressure.

Eclampsia, new-onset seizures in pregnancy, can complicate preeclampsia, a hypertensive pregnancy disorder. The mechanisms contributing to increased risk of seizures in preeclampsia are not fully known. One mechanism could be abnormal endocannabinoid system (ECS) activity and impaired neuromodulation. Indeed, increased placental cannabinoid receptor 1 (CB1R) expression and reduced serum anandamide, a CB1R ligand, have been reported in preeclampsia patients. We hypothesized that reduced uterine perfusion pressure (RUPP), used to mimic preeclampsia, leads to changes in hippocampal CB1R expression, and that manipulating CB1R activity will change seizure severity in RUPP mice. Pregnant mice underwent sham or RUPP surgery on gestational day (GD)13.5. On GD18.5, mice received: no drug treatment, pentylenetetrazol (PTZ, 40 mg/kg), Rimonabant (10 mg/kg) + PTZ, or 2-AG (1 mg/kg) + PTZ. Behaviors were video recorded (15 min for Rimonabant and 2-AG, followed by 30 min for PTZ), and the hippocampus was harvested. The expression of CB1R and ECS proteins was measured in hippocampal homogenates, synaptosomes, and cytosol. Hippocampal CB1R increased in homogenates and cytosolic fraction, and was unchanged in synaptosomes of RUPP mice. Increased CB1R colocalization on glutamate-releasing neurons within hippocampal CA1 was observed in RUPP mice. Rimonabant modestly increased seizure scores over time in RUPP mice. PTZ after rimonabant pretreatment increased seizure scores and duration, while reducing latency in sham mice, with little to no change in RUPP mice. Furthermore, RUPP mice had lower seizure scores over time than sham following CB1R blockade and activation. These data suggest that RUPP modifies CB1R activity prior to seizure induction, which protects mice from worse seizure outcomes.

Retinal Venule Coverage by Pericytes Decreases in Multiparous Mice in a Time-Dependent Manner Post-Delivery.

Structural changes in the retinal vasculature have been linked to increased cardiovascular risks and also change as a function of age. Because multiparity has been associated with poorer cardiovascular health scores, we hypothesized that changes in retinal vascular caliber would be observed in multiparous, compared to nulliparous, females and retired breeder males. Age-matched nulliparous (n = 6) and multiparous (n = 11, retired breeder females with 4 ± 1 litters), and male breeder (n = 7) SMA-GFP reporter mice were included for assessment of retinal vascular structure. Multiparous females had higher body mass, heart weight, and kidney weight compared to nulliparous mice, with lower kidney and higher brain weight compared to male breeders. There was no difference in number of retinal arterioles or venules, or arteriole or venule diameter among groups; however, venous pericyte density (number per venule area) decreased in multiparous vs. nulliparous mice and was negatively associated with the time since last litter and with age. Our results suggest that the time elapsed since delivery is an important factor to be considered in multiparity studies. Taken together, changes in vascular structure and potentially function, are time- and age-dependent. Ongoing and future work will determine whether structural changes are associated with functional consequences at the blood-retinal barrier.

Increased seizure sensitivity in pregnant mice with genetic knockdown of acid sensing ion channel 2a is associated with impaired hippocampal inflammatory response.

Acid sensing ion channels (ASICs) are mechano- and chemo-receptor channels that are activated by drops in extracellular pH as occurs after neurotransmission. In our previous study, we demonstrated that mice subjected to reduced utero-placental perfusion pressure during pregnancy, to mimic the pregnancy complication of preeclampsia, have reduced hippocampal expression of ASIC2a protein. We also showed that pregnant mice with heterozygous expression of ASIC2a (+/-) had increased sensitivity and severity to pentylenetetrazol-induced seizures; however, the mechanisms by which this occurs remain unclear. The purpose of this study was to investigate key molecular targets involving neurotransmission and inflammation that are differentially changed following seizure exposure in pregnant ASIC2a +/- mice. On gestational day 18.5, ASIC2a wild-type (+/+, n = 7) and +/- (n = 14) mice were injected with 40 mg/kg pentylenetetrazol and monitored for 30 min. Western blot and ELISA analysis revealed no difference in hippocampal synaptosome glutamate-related proteins but an increase in GABA concentration in pregnant +/- mice. Using ELISA and multiplex assays, we found a significant decrease in serum TNFα, and a decreased concentration of pro-inflammatory cytokines and chemokines in hippocampal cytosolic fraction. Significant reductions in IL-1ß, IL-3, IL-12 (p70), eotaxin, interferon gamma, and macrophage inflammatory protein (MIP-1ß), in the hippocampal cytosolic fractions of +/- mice were observed compared to +/+ mice. Additionally, there was no difference in hippocampal microglia density or activation in pregnant ASIC2a+/+ vs. +/- mice. These results support the hypothesis that pregnant mice with reduced ASIC2a may not be able to mount an inflammatory response following acute seizure exposure.

Redefining the cerebral autoregulatory range of blood pressures: Not as wide as previously reported.

This editorial summarizes the manuscript by Brassard and colleagues entitled, "Losing the dogmatic view of cerebral autoregulation". The main take-home message is that the cerebral autoregulatory plateau is much smaller than previously accepted and needs to be re-introduced as such.

Acid Sensing Ion Channel 2a Is Reduced in the Reduced Uterine Perfusion Pressure Mouse Model and Increases Seizure Susceptibility in Pregnant Mice.

Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure longevity and severity, the role of ASIC2a in mediating seizure sensitivity in pregnancy has not been investigated. We hypothesized that 1) RUPP reduces hippocampal ASIC2a, and 2) pregnant mice with reduced ASIC2a (ASIC2a+/-) have increased seizure sensitivity. On gestational day 18.5, hippocampi from sham and RUPP C57BL/6 mice were harvested, and ASIC2a was assessed using Western blot. Pregnant wild-type and ASIC2a+/- mice received 40 mg/kg of pentylenetetrazol (i.p.) and were video recorded for 30 min. Behaviors were scored using a modified Racine scale (0-7: 0 = no seizure; 7 = respiratory arrest/death). Seizure severity was classified as mild (score = 1-3) or severe (score = 4-7). RUPP mice had reduced hippocampal and placental ASIC2a protein. ASIC2a+/- mice had reduced latency to seizures, increased seizure duration, increased severe seizure duration, and higher maximum seizure scores. Reduced hippocampal ASIC2a in RUPP mice and increased seizure activity in pregnant ASIC2a+/- mice support the hypothesis that reduced ASIC2a increases seizure sensitivity associated with the RUPP.

Cerebral Blood Flow Regulation in Pregnancy, Hypertension, and Hypertensive Disorders of Pregnancy.

The regulation of cerebral blood flow (CBF) allows for the metabolic demands of the brain to be met and for normal brain function including cognition (learning and memory). Regulation of CBF ensures relatively constant blood flow to the brain despite changes in systemic blood pressure, protecting the fragile micro-vessels from damage. CBF regulation is altered in pregnancy and is further altered by hypertension and hypertensive disorders of pregnancy including preeclampsia. The mechanisms contributing to changes in CBF in normal pregnancy, hypertension, and preeclampsia have not been fully elucidated. This review summarizes what is known about changes in CBF regulation during pregnancy, hypertension, and preeclampsia.