Bumetanide induces post-traumatic microglia-interneuron contact to promote neurogenesis and recovery.

Although the Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders, the mechanism of action is obscure. Attention paid to elucidating the role of Nkcc1 has mainly been focused on neurons, but recent single cell mRNA sequencing analysis has demonstrated that the major cellular populations expressing NKCC1 in the cortex are non-neuronal. We used a combination of conditional transgenic animals, in vivo electrophysiology, two-photon imaging, cognitive behavioural tests and flow cytometry to investigate the role of Nkcc1 inhibition by bumetanide in a mouse model of controlled cortical impact (CCI). Here, we found that bumetanide rescues parvalbumin-positive interneurons by increasing interneuron-microglia contacts shortly after injury. The longitudinal phenotypic changes in microglia were significantly modified by bumetanide, including an increase in the expression of microglial-derived BDNF. These effects were accompanied by the prevention of CCI-induced decrease in hippocampal neurogenesis. Treatment with bumetanide during the first week post-CCI resulted in significant recovery of working and episodic memory as well as changes in theta band oscillations 1 month later. These results disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase in parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient GABA, resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.

Psychological First Aid Intervention after Exposure to a Traumatic Event at Work among Emergency Medical Services Workers.

Psychological First Aid (PFA) is a promising early intervention for managing mental health symptoms and providing psychosocial support after exposure to a traumatic event (TE) among high-risk organizations such as Emergency Medical Service (EMS). However, recipients' experience with PFA remains understudied. This study aimed to explore the perception of EMS workers (n = 13) who received PFA administered by a peer helper using a qualitative inductive approach. Findings from a thematic analysis indicated that the PFA intervention addresses EMS workers' immediate needs in congruence with Hobfoll's five essential principles to enhance coping and recovery after a TE. Specific components of the intervention, such as its time-sensitive nature and the closeness with peers, were especially appreciated by EMS workers. The PFA intervention appeared to have a beneficial impact on recipients, regarding the reduction of stigma, the increase of help-seeking behaviors, and the decrease of organizational difficulties. In conclusion, the PFA intervention offered by peer helpers is appreciated by recipients and is a beneficial first step toward supporting EMS workers in the aftermath of workplace trauma. These qualitative findings contribute to the current literature by informing further research about PFA intervention in other high-risk organizations and quantitative studies aiming to test PFA's efficacy in such settings.

Adherence to Psychological First Aid after Exposure to a Traumatic Event at Work among EMS Workers: A Qualitative Study.

Managing post-traumatic stress reactions in the first few days after exposure to a potentially traumatic event in the course of one's work remains a challenge for first responder organizations such as Emergency Medical Services (EMS). Psychological First Aid (PFA) is an evidence-informed approach to reducing initial distress and promoting short- and long-term coping strategies among staff in the aftermath of exposure. PFA provided by peer helpers is considered a promising solution for first responder organizations. Unfortunately, first responders may encounter stigma and barriers to mental health care. Therefore, a deeper investigation is needed regarding adherence over time to implemented PFA intervention. The purpose of this study is to qualitatively explore factors that influence adherence to PFA intervention of recipients and peer helpers. EMS workers (n = 11), working as PFA peer helpers for one year, participated in semi-structured interviews. Data were analyzed using thematic analysis; intercoder reliability (κ = 0.91) was also used. Researchers identified four themes and 11 subthemes influencing adherence to PFA intervention: (1) individual perceptions and attitudes of peer helpers and recipients about pfa intervention; (2) perceived impacts on peer helpers and recipients; (3) organizational support to pfa intervention; and (4) congruence with the occupational culture. Study findings herein suggest that it is conceivable to act on various factors to improve adherence to PFA intervention among peer helpers and recipients within EMS organization. This could lead to enhanced understanding of the challenges involved in sustaining a peer led PFA program for first responders.

Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression.

A striking result from epidemiological studies show a correlation between low alcohol intake and lower incidence for ischemic stroke and severity of derived brain injury. Although reduced apoptosis and inflammation has been suggested to be involved, little is known about the mechanism mediating this effect in vivo. Increase in intracellular chloride concentration and derived depolarizing GABAAR-mediated transmission are common consequences following various brain injuries and are caused by the abnormal expression levels of the chloride cotransporters NKCC1 and KCC2. Downstream pro-apoptotic signaling through p75NTR may link GABAA depolarization with post-injury neuronal apoptosis. Here, we show that changes in GABAergic signaling, Cl- homeostasis, and expression of chloride cotransporters in the post-traumatic mouse brain can be significantly reduced by administration of 3% ethanol to the drinking water. Ethanol-induced upregulation of KCC2 has a positive impact on neuronal survival, preserving a large part of the cortical peri-infarct zone, as well as preventing the massive post-ischemic upregulation of the pro-apoptotic protein p75NTR. Importantly, intracortical multisite in vivo recordings showed that ethanol treatment could significantly ameliorate stroke-induced reduction in cortical activity. This surprising finding discloses a pathway triggered by low concentration of ethanol as a novel therapeutically relevant target.

A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

OBJECTIVE: The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS. METHODS: APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes. RESULTS: APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect. INTERPRETATION: Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.