The diuretic Bumetanide and the birth hormone Oxytocin point to a common pathway in the early pathogenesis of Autism in rodents

Scientific papers  |  26 February 2014

The scientific community agrees on the early origin – fetal and/or early postnatal – of autism. The teams of Yehezkel Ben-Ari (CEO of Neurochlore and Emeritus Research Director at Inserm) at Neurochlore and at the Mediterranean Neurobiology Institute (Inmed), have just taken a new step in understanding the early manifestations of the disease. The researchers show in an article published in Science1 that the GABA developmental sequence is altered in two rodent models of autism. In control conditions, the activity of GABA, the main inhibitory neurotransmitter in the brain, follows a developmental sequence with GABA exciting neurons through type A GABA receptors (GABAAR) in early development and inhibiting them later in life, with a transient oxytocin-dependent inhibitory action during the critical period of birth. Ben-Ari’s teams show that in VPA rat and Fragile-X mouse models of autism, GABA’s action is excitatory at birth and remains so until two-weeks postnatally, when its activity should be inhibitory. GABA’s activity is dependent on the intracellular chloride concentration ([Cl]i) in neurons: when the concentration is high, GABA excites neurons, and when it is low, GABA inhibits them. The results in the rodent models of autism suggest that [Cl]i is high and remain high from birth. Treating the pregnant rodents one day before birth with Bumetanide, a diuretic and highly specific chloride importer inhibitor, restores the inhibitory shift at P15 in the offspring. These results provide a substrate to the successful phase II clinical trial to treat Autism with the diuretic in 20122.

References : 

1. Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates Autism pathogenesis in Rodent Offspring. Science. 2014, 343(6171):675-679. Doi: 10.1126/science.1247190

2. Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry. 2012, 2(12):e202. Doi: 10.1038/tp.2012.124