
Mutations in the PTEN gene lead to selective impairments in the development and function of inhibitory GABAergic neurons, while excitatory cholinergic neurons remain unaffected. Dietary supplementation with the ketone body β-hydroxybutyrate during early development can rescue these GABAergic deficits by inducing the activity of the FOXO transcription factor.


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A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including Autism Spectrum Disorders (ASDs).

Mutations in PTEN, the main negative regulator of the PI3K/Akt pathway, are strongly associated with ASD. However, it is unclear whether PTEN deficiencies can differentially affect inhibitory and excitatory signaling. Using the C. elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that daf-18 / PTEN mutations specifically impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The specific defects observed in the GABAergic system in daf-18/PTEN mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. Importantly, we found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO, therefore improving GABAergic neurodevelopment and function in daf-18/PTEN mutants. Our study provides fundamental insights linking PTEN mutations and neurodevelopmental defects and delves into the mechanisms underlying KGDs’ positive effects on neuronal disorders characterized by E/I imbalances.

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### Competing Interest Statement

The authors have declared no competing interest.

 [1]: pending:yes

The ketone body β-hydroxybutyrate rescues neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants

dietary-ketone-body-supplementation-rescues-gabaergic-deficits-in-c-elegans-pten-mutants


Dietary Ketone Body Supplementation Rescues GABAergic Deficits in C. elegans PTEN Mutants
