Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors.

Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5'-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Glucocorticoid Receptor-Dependent Astrocytes Mediate Stress Vulnerability.

BACKGROUND: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. METHODS: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. RESULTS: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release. CONCLUSIONS: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.

Clinical factors that influence the outcome of selective devascularization in the treatment of portal hypertension.

There is a high incidence of death due to variceal hemorrhage in patients with portal hypertension. Factors to consider when choosing selective devascularization in the treatment of variceal hemorrhage remain a controversy. This study aims to generate the prevalent clinical risk factors that affect the outcomes of selective devascularization procedures. Elucidating these features may guide future treatment of esophageal varices in patients with portal hypertension. We retrospectively analyzed medical records of 455 patients who underwent selective devascularization procedures in our center. Patients were subject to splenectomy, selective devascularization with or without esophageal transection. The mode of surgery recurred in comparable rates in both the group with major complications postoperatively (high-risk group which consisted of 63 patients) or the group without major postoperative complications (low-risk group, 392). Risk factors that negatively influenced outcomes of surgery include severe symptoms (89% in high risk group and 71% in low risk group), large volume of blood loss in the hemorrhage before surgery (81% in high risk group and 16% in low risk group), sever liver cirrhosis (83% in high risk group and 67% in low risk group), previous endotherapy, prolonged prothrombin time, and poor liver function. Selective devascularization is a feasible option to treat variceal hemorrhage in patients with portal hypertension.

Dumbbell-shaped cervical spinal neurilemmoma presenting as neck mass.

Cervical neurilemmoma may originate from any nerve sheath tissue in the neck including the vagus nerve, glossopharyngeal nerve, brachial plexus, sympathetic trunk and cervical spine. We report an unusual case of a dumbbell-shaped neurilemmoma arising from the cervical spinal roots in a patient who complained of having had a neck mass for several months. Computed tomographic scan and magnetic resonance imaging revealed a dumbbell-shaped tumour extending from the C4 spinal level through the intervertebral foramen into the right parapharyngeal space. Decompression surgery was performed first via the cervical approach. Five months later, the patient received laminectomy and a complete tumour excision. The symptoms and signs were significantly relieved without neurological sequelae. No evidence of recurrence was noted after one-year follow up. This two-staged operation could offer an alternative surgical approach yielding ideal therapeutic results in such a rare disease.