KBMMGABA

Ketone Body Mediated Modulation of GABAergic Signaling: Mechanisms and Consequences

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 Obiettivo del progetto (Objective)

'The brain’s high metabolic requirements mean that the mantra of nutritionists worldwide, “You are what you eat!” could be more accurately phrased, “you are what your brain metabolises!”. While glucose provides the major source of energy for the brain, ketone bodies (KBs) also play a critical role during the neonatal period, during fasting and during periods of metabolic stress (1,2,3). The ability of KBs to powerfully modulate neuronal activity is highlighted by the fact that the ketogenic diet has been used for the management of “difficult -to-control” seizures since the 1920s (4,5), and is currently undergoing trials for the management of a variety of neurodegenerative disorders (6). However, neither the molecular mechanisms by which ketone bodies act, nor the role of KBs during normal development and physiology are known. In vitro studies in a wide variety of animal species and brain structures, indicate that GABAergic signalling is depolarising during the early neonatal period (7). However, preliminary results, in vitro and in vivo, suggest that KBs induce a decrease in [Cl-]i and consequently a hyperpolarising shift in GABAergic signalling in neonates. In this project we will study both the mechanisms of this KB mediated effect and its consequences for neuronal network activity in vivo.'

Introduzione (Teaser)

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.

Descrizione progetto (Article)

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.