Early expression of autism spectrum disorder in experimental animals

  • Awarded: 2011
  • Award Type: Explorer
  • Award #: 230267

Autism is a developmental disorder that is most likely triggered during prenatal or early postnatal life. Yehezkel Ben‐Ari and his colleagues at the Mediterranean Institute of Neurobiology and the pharmaceutical company Neurochlore, in France, aim to identify the earliest signals of autism that can be detected in the operation of developing brain networks.

In 1989, Ben-Ari and his team discovered that the neurotransmitter gamma-aminobutyric acid (GABA) excites immature neurons, which have a high concentration of intracellular chloride. This chloride concentration progressively declines throughout fetal development, and then during labor, the hormone oxytocin triggers an abrupt shift that inhibits the excitatory effects of GABA. This inhibitory shift at birth has a major neuroprotective and analgesic effect, and an absence of this shift leaves the brain more susceptible to injury if the newborn is deprived of oxygen.

An increase in intracellular chloride is a common signature of many brain disorders in which GABA-induced excitement of neurons leads to seizures and aberrant patterns of activity. Relying on this observation, Ben-Ari and his colleagues tested the effects of a diuretic on children with autism and found a reduction in the severity of symptoms after three months of treatment. They have finished a double-blind randomized study involving 54 children with autism and found a significant amelioration of many symptoms, notably social communication deficits. The team is planning to perform a multi-center trial across the European Union.

The researchers are using animal models of autism to test the hypothesis that the developmental sequence involving GABA is altered or delayed in the disorder. They plan to use several recording techniques, including single-channel recording, and a variety of animal models of autism, such as the in utero valproate model. The demonstration of alterations in the GABA developmental sequence during brain maturation could have important implications for understanding and treating the disorder.

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