Astrocyte atrophy induced by L-PGDS/PGD2/Src signaling dysfunction in the central amygdala mediates postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a serious psychiatric disorder that has significantly adverse impacts on maternal health. Metabolic abnormalities in the brain are associated with numerous neurological disorders, yet the specific metabolic signaling pathways and brain regions involved in PPD remain unelucidated. METHODS: We performed behavioral test in the virgin and postpartum mice. We used mass spectrometry imaging (MSI) and targeted metabolomics analyses to investigate the metabolic alternation in the brain of GABAAR Delta-subunit-deficient (Gabrd-/-) postpartum mice, a specific preclinical animal model of PPD. Next, we performed mechanism studies including qPCR, Western blot, immunofluorescence staining, electron microscopy and primary astrocyte culture. In the specific knockdown and rescue experiments, we injected the adeno-associated virus into the central amygdala (CeA) of female mice. RESULTS: We identified that prostaglandin D2 (PGD2) downregulation in the CeA was the most outstanding alternation in PPD, and then validated that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2 downregulation plays a causal role in depressive behaviors derived from PPD in both wild-type and Gabrd-/- mice. Furthermore, we verified that L-PGDS/PGD2 signaling dysfunction-induced astrocytes atrophy is mediated by Src phosphorylation both in vitro and in vivo. LIMITATIONS: L-PGDS/PGD2 signaling dysfunction may be only responsible for the depressive behavior rather than maternal behaviors in the PPD, and it remains to be seen whether this mechanism is applicable to all depression types. CONCLUSION: Our study identified abnormalities in the L-PGDS/PGD2 signaling in the CeA, which inhibited Src phosphorylation and induced astrocyte atrophy, ultimately resulting in the development of PPD in mice.

Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons.

BACKGROUND AND PURPOSE: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects. EXPERIMENTAL APPROACH: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d-/-) mice were used to confirm the requirement of GluN2D for the antidepressant effects. KEY RESULTS: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d-/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect. CONCLUSION AND IMPLICATIONS: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

Molecular basis of ClC-6 function and its impairment in human disease.

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

Postoperative residual neuromuscular block in a woman with severe preeclampsia treated with magnesium sulfate and nicardipine: A case report and literature review.

Calcium channel blockers and magnesium sulfate are frequently used together, particularly in women with underlying chronic hypertension and pre-eclampsia. A review of the literature showed prolonged neuromuscular blockade after treatment with magnesium sulfate. Since magnesium and calcium have opposite effects on the neuromuscular junctions, muscle weakness may become a postoperative manifestation of magnesium sulfate and calcium antagonist treatment in the obstetric population; however, limited information is available regarding this postulation. Here, we report a case wherein rocuronium activity was markedly prolonged due to pretreatment with magnesium sulfate and nicardipine after general anesthesia during an emergency cesarean delivery.

Ultrasound-Assisted Technology Versus the Conventional Landmark Location Method in Spinal Anesthesia for Cesarean Delivery in Obese Parturients: A Randomized Controlled Trial.

BACKGROUND: Spinal anesthesia, which is commonly used in cesarean deliveries, is often difficult to perform in obese parturients because of poorly palpable surface landmarks and positioning challenges. This study aimed to evaluate the benefits of ultrasound-assisted technology for performing spinal anesthesia in obese parturients. METHODS: Parturients with a body mass index (BMI) ≥30 kg/m scheduled for elective cesarean delivery were randomized to undergo spinal anesthesia using the conventional landmark location technique (landmark group, n = 40) or prepuncture ultrasound examination (ultrasound group, n = 40). All participants underwent spinal anesthesia in the lateral position. The primary outcome was the first-attempt success rate. Secondary outcomes were the number of skin punctures and needle passes, procedure times, patient satisfaction, changes in the intended interspace, and incidence of complications. RESULTS: The ultrasound group had a significantly higher first-attempt success rate (87.5% vs 52.5%; P = .001), fewer cases requiring >10 needle passes (1 vs 17; P < .001), and fewer skin punctures and needle passes (P < .001 for both). There was no statistically significant difference in the time taken to identify the needle insertion site between the 2 groups (202.5 vs 272.0 seconds; P = .580). Both the spinal injection time and total procedure time were significantly longer in the landmark group (P < .001). Patient satisfaction scores were significantly higher in the ultrasound group (P = .001). Among patients with BMI between 30 and 34.9 kg/m, there was no statistically significant difference in the first-attempt success rate (P = .407), number of cases with >10 needle passes (P = .231), spinal injection time (P = .081), or total procedure time (P = .729); however, more time was required to identify the needle insertion site in the ultrasound group (P < .001). For patients with BMI between 35 and 43 kg/m, the ultrasound group had a significantly higher first-attempt success rate (P ≤ .041), fewer cases with >10 needle passes (P ≤ .01), and shorter procedure times, including the time required to identify the needle insertion site (P < .001). CONCLUSIONS: Prepuncture ultrasound examination can facilitate spinal anesthesia in the lateral position in obese parturients (35 kg/m ≤ BMI ≤ 43 kg/m) by improving the first-attempt success rate, reducing the number of needle passes and puncture attempts, shortening the total procedure time, and improving patient satisfaction.

Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

Sevoflurane is one of the most commonly used volatile anaesthetics for children, but the safety of prolonged or repeated clinical use of sevoflurane in infants or children is controversial. Here, we investigated the effects of sevoflurane on rats in early life and the time scale of those effects. Our behavioral results indicated that repeated short-term exposure of new-born rats to sevoflurane caused learning and memory impairment, while a single exposure of rats to sevoflurane was relatively safe. Further mechanistic investigation revealed that repeated sevoflurane exposure impaired long-term potentiation (LTP), downregulated the expression of certain synaptogenesis-related proteins (GluR1, PSD95) and upregulated proteins related to endoplasmic reticulum (ER) stress in the hippocampus. An ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the changes in the levels of synaptic plasticity proteins. Our results provide new evidence for the clinical concerns regarding repeated sevoflurane anesthesia.

Identification of Intracellular ß-Barrel Residues Involved in Ion Selectivity in the Mechanosensitive Channel of Thermoanaerobacter tengcongensis.

The mechanosensitive channel of small conductance (MscS) is a bacterial membrane pore that senses membrane tension and protects cells from lysis by releasing osmolytes. MscS is a homoheptameric channel with a cytoplasmic domain with seven portals and a ß-barrel opening to the cytoplasm. TtMscS, an MscS channel from Thermoanaerobacter tengcongensis, is an anion-selective channel. A previous study from our laboratory has defined the crucial role of ß-barrel in the anion selectivity of TtMscS (Zhang et al., 2012). However, the mechanistic details by which the ß-barrel determines anion selectivity remain unclear. Here, using mutagenesis and patch-clamp recordings, we investigated the function and structural correlations between ß-barrels and the anion selectivity of TtMscS at the atomic level. Our results indicated that mutation of V274, a residue at the center of the inner wall of the ß-barrel in TtMscS, caused the anion selectivity of TtMscS reverse to cation selectivity. Moreover, the electrostatic potential (T272) and physical size (L276) of residues in the inner wall of ß-barrel also determine the anion selectivity of TtMscS. In summary, the present study confirmed that the ß-barrel region of TtMscS acts as a "selective filter" that renders TtMscS anion selectivity.

Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD.

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.