Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring”

Bambini-Júnior, Victorio; Nunes, Gustavo Della-Flora; Schneider, Tomasz; Gottfried, Carmem

doi:10.1126/science.1255679

Cited by 6 publications

(5 citation statements)

References 15 publications

(10 reference statements)

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“…Based on these hypotheses, reducing the [Cl − ] i via BTN proved efficacious in an animal model of autism using valproic acid exposure (Tyzio et al, 2014). In a commentary response to this study, however, it was noted that it is premature to consider BTN as a prenatal intervention suitable for ASD due to the lack of proper technical tests and failures to assess the long lasting modifications (Bambini-Junior et al, 2014).…”

Section: Systemic Effectsmentioning

confidence: 99%

Off-Label Use of Bumetanide for Brain Disorders: An Overview

2019

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Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl − gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl − importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl − levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.

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Section: Systemic Effectsmentioning

confidence: 99%

Off-Label Use of Bumetanide for Brain Disorders: An Overview

2019

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“…W e are very grateful to Bambini-Junior et al (1) for raising the issues of (i) the long-lasting effect on behavior of bumetanide pretreatment in rodent models of autism, (ii) the long-lasting effect on behavior of blocking oxytocin signaling in naïve mothers during the delivery period, and (iii) the sex-dependent response to bumetanide treatment. We are glad to respond with additional experimental observations.…”

Section: 2mentioning

confidence: 99%

Response to Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring”

Eftekhari

Shahrokhi

Tsintsadze

et al. 2014

Science

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Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of g-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth. (1) for raising the issues of (i) the long-lasting effect on behavior of bumetanide pretreatment in rodent models of autism, (ii) the long-lasting effect on behavior of blocking oxytocin signaling in naïve mothers during the delivery period, and (iii) the sex-dependent response to bumetanide treatment. We are glad to respond with additional experimental observations.To evaluate whether maternal pretreatment with bumetanide has long-term behavioral effects, we have now evaluated adult behavior in two animal models of autism: rats exposed in utero to valproate (VPA rats) and mice carrying the fragile X mutation (FRX mice). Because VPA rats have been shown to display altered behavior (2-4), using the social approach-avoidance paradigm (2) we show that VPA male adult rats that received bumetanide 1 day before birth (maternal pretreatment) (5) display improved sociability (Fig. 1A), spending significantly more time in the social chamber than age matched nontreated VPA rats. Conversely, it has been shown that FRX mice have similar sociability to wild-type (WT) mice in the three-chamber social test (6), thereby precluding the use of this paradigm to test the effects of bumetanide. Therefore, we evaluated stereotypical behavior (7), and adult FRX male mice displayed a significantly higher number of grooming events (bouts) than WT littermates (Fig. 1B). Maternal pretreatment with bumetanide of FRX mice restored the grooming behavior (Fig. 1B). Therefore, in the valproate and fragile X rodent models of autism, maternal pretreatment with bumetanide 1 day before birth restores control behavioral phenotypes in adult offspring.We further evaluated the effect of blocking oxytocin receptors with maternal pretreatment of naïve mothers 1 day before delivery with SSR126768A (SSR) (5) on adult social behavior in mice and rats (2, 8). We observed that adult rat (Fig. 1C) and mouse ( Fig. 1D) offspring exposed to SSR display lower sociability than controls, extending our earlier observations (5) to adulthood. Thus, blocking oxytocin signaling in naïve mothers during the delivery period produced adult offspring with altered social behavior.In addition to our behavioral tests in adult animals, we wanted to verify the presence of network alterations in the developing brain of FRX mice, as we did for the VPA rats (5). We therefore performed extracellular intracranial electroencephalographic (EEG) recordings in vivo in the hippocampal CA3 area of head-restrained P14 and P15 WT and FRX mice. We show prominent differences in the oscillatory activity of FRX mice compared with WT (Fig. 1E1). There was a significant decrease in slow oscillatory activity (0.1 to 4 Hz) in co...

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“…a mutation, a drug or a treatment) gives for an instance a motoric manifestation, this will indeed affect spatial memory performance, whether or not higher cognitive functioning is preserved. A similar effect on anxiety and other behaviors would also be expected (Bannerman et al, 2014). This of course does not imply that there could not be deficits in higher cognitive functioning without physical conditions nor that anxiety is required for these deficits to manifest.…”

Section: Research With Clinical Translational Validitymentioning

confidence: 62%

“…Moreover, the basic assessment of social interaction abilities in rodents involves measurements of specific behaviors such as sniffing, following, climbing on, ultrasonic vocalizations, allogrooming, fighting, and sexual behavior while two unfamiliar adults freely interact in an open-field arena (Bambini-Junior et al, 2014;File and Hyde, 1978;File and Seth, 2003;Hirsch et al, 2018;Huang et al, 2014;More, 2008;Silverman et al, 2010). Under these settings, many genetic, pharmacological, developmental and neurobiological rodent models have been shown to exhibit perturbations in social interaction (Hida et al, 2013;Koros et al, 2007;Millan and Brocco, 2008;Peleg-Raibstein et al, 2012;Pratt et al, 2012;Sams-Dodd, 1999).…”

Section: Social Cognitionmentioning

confidence: 99%