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


Core Concepts
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.
Abstract
This study demonstrates that mutations in the C. elegans PTEN ortholog daf-18 result in specific defects in the development and function of inhibitory GABAergic neurons, without affecting excitatory cholinergic neurons. The key findings are: daf-18/PTEN mutants exhibit hypersensitivity to cholinergic drugs, reduced body shortening in response to touch, and deficits in the execution of the omega turn escape response - all of which are indicative of impaired GABAergic signaling. The GABAergic deficits in daf-18 mutants are due to reduced activity of the FOXO transcription factor DAF-16 during neurodevelopment, leading to morphological abnormalities in GABAergic motor neuron commissures. Dietary supplementation with the ketone body β-hydroxybutyrate (βHB) during early development can rescue the GABAergic defects in daf-18 mutants by inducing DAF-16/FOXO activity. This dietary intervention improves both the morphology and function of GABAergic neurons. The rescuing effects of βHB are critically dependent on the early developmental stages, as exposure during later juvenile stages is less effective. These results provide fundamental insights into how PTEN mutations can selectively impact inhibitory neurotransmission, and demonstrate the potential of ketogenic diets to mitigate neurodevelopmental defects associated with PTEN deficiency.
Stats
Mutations in daf-18/PTEN lead to hypersensitivity to the cholinergic drugs aldicarb and levamisole. daf-18 and daf-16 mutants exhibit reduced body shortening in response to touch, indicative of GABAergic deficits. daf-18 and daf-16 mutants show a decreased proportion of closed omega turns during the escape response. Optogenetic activation of GABAergic neurons elicits reduced elongation in daf-18 and daf-16 mutants compared to wild-type. Optogenetic activation of cholinergic neurons causes hypercontraction in daf-18 and daf-16 mutants. daf-18 and daf-16 mutants exhibit increased frequency of morphological defects in GABAergic neuron commissures.
Quotes
"daf-18/PTEN deficiency in C. elegans results in a specific impairment of inhibitory GABAergic signaling, while the excitatory cholinergic signaling remains unaffected." "The dysfunction of GABAergic neurons in these mutants arises from the inactivity of the transcription factor DAF-16/FOXO during their development, resulting in conspicuous morphological and functional alterations." "A diet enriched with the ketone body β-hydroxybutyrate, which induces DAF-16/FOXO activity, mitigates the functional and morphological defects in the development of GABAergic neurons." "β-hydroxybutyrate supplementation during the early stages of development is both necessary and sufficient to achieve these rescuing effects on GABAergic signaling in daf-18/PTEN mutants."

Deeper Inquiries

How might the interplay between PTEN, integrin signaling, and the FOXO pathway contribute to the selective impairment of GABAergic neuron development observed in this study

The interplay between PTEN, integrin signaling, and the FOXO pathway likely contributes to the selective impairment of GABAergic neuron development observed in this study through a complex network of interactions. PTEN, as a negative regulator of the PI3K/Akt pathway, plays a crucial role in modulating cellular processes such as growth, proliferation, and survival. Mutations in PTEN can lead to dysregulation of this pathway, impacting downstream effectors like FOXO transcription factors. In the context of neuronal development, PTEN deficiency may result in aberrant activation of Akt and subsequent inhibition of FOXO, affecting the transcription of genes involved in neuronal differentiation and function. Integrin signaling, on the other hand, is known to play a role in cell adhesion, migration, and neurite outgrowth. Integrins are cell surface receptors that interact with the extracellular matrix and mediate signaling cascades that influence various cellular processes. The crosstalk between integrin signaling and the PI3K/Akt pathway has been reported in different cellular contexts, suggesting potential interactions in neuronal development as well. Disruption in integrin signaling, possibly due to PTEN mutations, could impact neuronal guidance, axonal pathfinding, and synapse formation, contributing to the observed defects in GABAergic neurons. The FOXO pathway, regulated by PTEN and Akt, is a key player in neuronal development and function. FOXO transcription factors control the expression of genes involved in cell cycle regulation, apoptosis, and stress response. In the context of GABAergic neuron development, the dysregulation of FOXO activity due to PTEN mutations may lead to altered expression of genes critical for neuronal differentiation, synaptogenesis, and neurotransmitter release. The interplay between PTEN, integrin signaling, and the FOXO pathway likely creates a complex regulatory network that influences the selective impairment of GABAergic neuron development in this study.

What other molecular mechanisms, beyond HDAC inhibition and insulin/IGF-1 signaling, could mediate the beneficial effects of ketone bodies on neurodevelopmental disorders characterized by E/I imbalances

Beyond HDAC inhibition and insulin/IGF-1 signaling, several other molecular mechanisms could mediate the beneficial effects of ketone bodies on neurodevelopmental disorders characterized by E/I imbalances. One potential mechanism is the modulation of mitochondrial function and oxidative stress. Ketone bodies, such as β-hydroxybutyrate, serve as alternative energy substrates that can enhance mitochondrial function and reduce oxidative stress, which are crucial for neuronal health and function. Improved mitochondrial metabolism and reduced oxidative stress can promote neuronal survival, synaptic plasticity, and neurotransmitter balance, contributing to the overall improvement in neuronal function. Another possible mechanism is the regulation of neuroinflammation and immune responses. Ketone bodies have been shown to possess anti-inflammatory properties and can modulate immune cell function in the brain. Neuroinflammation is increasingly recognized as a contributing factor to neurodevelopmental disorders, and the anti-inflammatory effects of ketone bodies may help mitigate neuroinflammatory processes, thereby promoting a healthier neuronal environment and function. Furthermore, ketone bodies can influence epigenetic modifications, such as DNA methylation and histone acetylation, which play a crucial role in gene expression regulation during neuronal development. By altering the epigenetic landscape, ketone bodies may promote the expression of genes involved in neurodevelopment and synaptic plasticity, leading to improved neuronal connectivity and function. Overall, the multifaceted effects of ketone bodies on mitochondrial function, oxidative stress, neuroinflammation, immune responses, and epigenetic regulation provide a comprehensive framework for understanding their beneficial effects on neurodevelopmental disorders characterized by E/I imbalances.

Given the critical developmental window for the rescuing effects of β-hydroxybutyrate, what are the potential implications for the timing and delivery of ketogenic dietary interventions in the clinical management of PTEN-associated neurodevelopmental disorders

The critical developmental window for the rescuing effects of β-hydroxybutyrate has significant implications for the timing and delivery of ketogenic dietary interventions in the clinical management of PTEN-associated neurodevelopmental disorders. Understanding the optimal timing for initiating ketogenic dietary interventions is crucial for maximizing their therapeutic benefits. The findings suggest that exposure to β-hydroxybutyrate during early developmental stages, particularly at the L1 larval stage, is most effective in ameliorating the neurodevelopmental defects associated with PTEN mutations. These results highlight the importance of early intervention with ketogenic diets in individuals with PTEN-associated neurodevelopmental disorders to prevent or mitigate the development of GABAergic neuronal deficits. Clinically, this implies that dietary interventions should be initiated as early as possible, ideally during critical periods of neurodevelopment, to achieve the best outcomes. Healthcare providers and caregivers should be aware of the importance of timing in implementing ketogenic diets as part of the treatment plan for individuals with PTEN mutations. Moreover, the findings suggest that sustained exposure to β-hydroxybutyrate throughout the critical developmental window may be necessary to maintain the beneficial effects on GABAergic neuron development. This underscores the importance of consistent and continuous dietary management to support optimal neurodevelopment in individuals with PTEN-associated neurodevelopmental disorders. Additionally, the results emphasize the need for personalized and tailored dietary interventions based on the specific developmental stages and individual characteristics of patients to optimize the therapeutic outcomes of ketogenic diets in the clinical management of PTEN-associated neurodevelopmental disorders.
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