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Ketone Body Mediated Modulation of GABAergic Signaling: Mechanisms and Consequences

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Food for thought in the developing brain

Current research is providing information on sources of energy for brain activity and central nervous system development in newborn babies. One of the many applications promises to be new therapies for epilepsy.


Ketone bodies are soluble products from fatty acid breakdown and can be used for energy in the brain under certain circumstances such as fasting. Although termed 'bodies', they are soluble substances and include acetone and acetoacetic acid. An EU-funded project, 'Ketone body mediated modulation of gabaergic signaling: mechanisms and consequences' (KBMMGABA), has just concluded some fascinating research into the role of ketone bodies in brain development during the first weeks of a baby's life. During early development, silent nerve cells shift to become coactive networks that operate via thousands of synapses due to the action of gamma-aminobutyric acid (GABA). One of many neurotransmitters, GABA acts primarily via an outflow of chloride exciting the action of nerve cells. At later stages, the action of GABA causes a decrease in neonatal cortical activity. In adults, nerve cells producing GABA, GABAergic neurons, have an inhibitory effect. KBMMGABA scientists showed that cannabinoids can suppress GABAergic inhibition. The cannabinoids bind to receptor molecules resulting in suppression of GABA release. Furthermore, initial results suggest that ketone bodies mediate a decrease in intracellular chloride reducing GABA signalling in neonates and activity in the cortex region of the brain. Ketone body concentrations are elevated in developing babies. Future research could focus on additional energy sources including ketone bodies, lactate and pyruvate to artificial cerebrospinal fluid to mimic the conditions in the neonatal brain. Both lactate and pyruvate can cause a decrease in brain activity in the cortex. This may serve to give a clear picture after very recent research revealed that ketone bodies do not have an effect on chloride levels under certain circumstances and the changes in brain activity may be due to acidification. Continuation of the work achieved by KBMMGABA project will be crucial in developing new therapies for epilepsies. Further research into high levels of lactate found during prenatal and pre-suckling periods could also be invaluable for treatment of neonatal pathologies such as hypoxia and trauma as well as seizures.

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