Caenorhabditis elegans worm with GABAergic neurons labelled in red. Image credit: Sebastian Giunti (CC BY 4.0)
To work optimally, the brain needs to delicately balance excitation and inhibition – that is, it must precisely control exactly when and how excitatory neurons (which activate the system) or inhibitory ones (which counteract these activating signals) are switched on. Neurological disorders can arise when this equilibrium is disrupted, for example when defects are present in an inhibitory signalling system that relies on a molecule known as GABA. More recently, a gene known as PTEN has also emerged as playing an important role during the development of the nervous system, yet exactly why this is the case has remained unclear.
To explore this question, Giunti et al. focused on the neuromuscular system of the roundworm Caenorhabditis elegans, in which excitatory (‘cholinergic') and inhibitory (‘GABAergic’) neurons control how muscles contract and relax. A range of biological approaches were used to assess the impact of PTEN deficiencies on this system. This revealed that mutations in this gene do not impact cholinergic activity; they did, however, lead to diminished GABAergic activity. Overall, this resulted in an increased ratio of excitatory to inhibitory activity in the system.
Further work showed that, in the mutated worms, the suppression of inhibitory neurons was due to a specific protein being inactive during early development. This transcription factor is the worm equivalent of the human FOXO protein, and it helps to turn genes on and off during development. Its inactivity is linked to noticeable changes in the shape and activity of GABAergic neurons.
In humans, medical ketogenic diets (which force the body to use fats rather than sugars as a source of energy) are known to improve conditions linked to imbalances in the excitatory and inhibitory systems. Giunti et al. therefore investigated whether a similar approach could mitigate some of the defects seen in PTEN mutants. Exposing these worms early in development to a type of molecule produced in ketogenic diets partly improved the state of their GABAergic neurons.
Taken together, this work suggests a potential molecular basis for the association between PTEN and the balance between excitatory and inhibitory activity. As PTEN mutations are often found in individuals diagnosed with autism spectrum disorders, further research is necessary to validate these findings in mammals and explore their clinical relevance.
