Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

 In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."



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Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour : Nature

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.

Gut Bacteria Consumes Neurochemical (GABA) Linked To Depression

A recently-discovered strain of gut bacteria has been found to consume GABA, a neurochemical found in the brain. The neurotransmitter has a calming effect on the brain, and the bacteria’s reliance on GABA could explain how the microbiome has an effect on mood.

The bacterial species found in the gut – called KLE1738 – was found to grow in culture only when supplemented with GABA molecules. “Nothing made it grow, except GABA,” said Philip Strandwitz, a postdoctoral research associate from Northeastern University in Boston. Strandwitz and his colleagues presented their findings at the annual meeting of the American Society for Microbiology, in June.

This is the first time a bacterial species has been found which uses a neurotransmitter as an energy source. As GABA calms down brain activity by inhibiting signals between nerve cells, the researchers were surprised to find that it’s necessary for some microbial life.

Psychobiotics: How gut bacteria mess with your mind: Microbe world

How exactly do gut bacteria influence the brain? The mechanisms are
becoming clear. The bacterium Lactobacillus rhamnosus, which is used in
dairy products, has potent anti-anxiety effects in animals, and works by
changing the expression of GABA receptors in the brain. These changes
are mediated by the vagus nerve, which connects the brain and gut. When
this nerve is severed no effect on anxiety or on GABA receptors is seen
following psychobiotic treatment with L. rhamnosus.

The Brain Makes Its Own Version Of Valium

The protein is known as diazepam binding inhibitor, or DBI. It calms the rhythms of a key brain circuit and so could prove valuable in developing novel, less side-effect-prone therapies not only for epilepsy but possibly for anxiety and sleep disorders, too. The researchers' discoveries were published in the journal Neuron.

PLOS Pathogens: GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii

During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondiifor spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABA_Areceptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABA_A receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DCin vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens.
See also the T.Gondii host/pathogen interactome

MicrobeWorld - Intestinal bacteria produce neurotransmitter (GABA), could play role in inflammation

We identified, to our knowledge, the first bifidobacterial strain, Bifidobacterium dentium, that is capable of secreting large amounts of gamma-aminobutyric acid (GABA). This molecule is a major inhibitory neurotransmitter in the central and enteric nervous systems, says Karina Pokusaeva, a researcher on the study and a member of the laboratory of James Versalovic.