Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target.

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.

Heterogeneous subpopulations of GABAAR-responding neurons coexist across neuronal network scales and developmental stages in health and disease.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population average level during typical neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.

Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors.

Oxaliplatin is a cornerstone chemotherapeutic used in the treatment of colorectal cancer, the third leading cause of death in Western countries. Most side effects of this platinum-containing drug are adequately managed in the clinic, although acute and long-term neurotoxicity still severely compromises the quality of life of patients treated with oxaliplatin. We have previously demonstrated that therapeutically relevant concentrations/doses of oxaliplatin lead to a reduction in intracellular pH in mouse dorsal root ganglion (DRG) neurons in vitro and in vivo and that this alteration sensitizes TRPA1 and TRPV1 channels, which most likely mediate the allodynia associated with treatment. In this study, we show that oxaliplatin leads to a reduction of intracellular pH by forming adducts with neuronal haemoglobin, which acts in this setting as a proton buffer. Furthermore, we show that FDA-approved drugs that inhibit carbonic anhydrase (an enzyme that is linked to haemoglobin in intracellular pH homeostasis), ie, topiramate and acetazolamide, revert (1) oxaliplatin-induced cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons in culture, (2) oxaliplatin-induced cytosolic acidification of DRG of treated animals, and (3) oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity on cancer cells. Our data would therefore suggest that reversal of oxaliplatin-induced cytosolic acidification is a viable strategy to minimize acute oxaliplatin-induced symptoms.

A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy.

STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions.This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper.

Oxaliplatin induces pH acidification in dorsal root ganglia neurons.

Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold-induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin. Reversal of the acidification indeed leads to a significantly reduced activity of TRPA1 channels. Last, acidification occurs also in vivo after a single injection of therapeutically-relevant doses of oxaliplatin.