The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Although the etiology of ASD remains elusive, converging lines of research indicate that mitochondrial dysfunction may play a substantive role in disease pathophysiology. Without an established causal link, the generation of therapeutic targets for ASD has been relatively unsuccessful and has focused solely on individual symptoms. The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has previously been used for the treatment of intractable epilepsy and is known to enhance mitochondrial function. The purpose of this study was to determine if the KD could reverse the social deficits and mitochondrial dysfunction identified in the prenatal valproic acid (VPA) rodent model of ASD. Sprague-Dawley dams were administered VPA or saline on gestational day 12.5. The pups were treated with the KD or their standard diet (SD) for 10 days beginning on postnatal day 21 (PD21). On PD35 juvenile play behavior was tested with the play-fighting paradigm and rats were then sacrificed for mitochondrial bioenergetic analysis. The offspring exposed to VPA prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD. Prenatal VPA exposure also disrupted the pattern of play responses; VPA/SD animals used complete rotations more often than saline control animals. Treatment with the KD did not affect the number of complete rotations. In addition, while prenatal exposure to VPA altered mitochondrial respiration, the KD was able to restore aspects of bioenergetic dysfunction. As the KD was able to modify complex social behaviors and mitochondrial respiration, it may be a useful treatment option for ASD. Future studies will need to examine the effectiveness of the KD to reverse the two additional core deficits of ASD and to explore various treatment regimens to determine optimal treatment duration and formulation.

The Current Status of the Ketogenic Diet in Psychiatry

“…It is also believed that mitochondrial dysfunction may play a role in the onset of ASD (35). Ahn et al (43) aimed to determine if KD could reverse the social deficits and mitochondrial dysfunction seen in a prenatal VPA animal model of autism using Wistar rats. On postnatal day 21, rats were placed on either KD (6:1 lipid:non-lipid ratio) or standard diet for 10–14 days.…”

“…Beta-hydroxybutyrate was measured. KD had a significant effect and was able to modify complex social behaviors in VPA and control rats and mitochondrial respiration (43). …”

An energetic view of stress: Focus on mitochondria

“…For example, treatment with a ketogenic diet – a high-fat low-carbohydrate diet that enhances mitochondrial function – was able to ameliorate impaired mitochondrial respiration and deficits in social behaviors in a valproic acid model of autism in rats (Ahn et al, 2014). In another study, acute infusion in rodents of resveratrol, a compound that activates AMPK-induced mitochondrial biogenesis, counteracted diminished sociability induced by peripubertal stress (Poirier et al, 2014).…”

Increased expression of fatty acid synthase and acetyl-CoA carboxylase in the prefrontal cortex and cerebellum in the valproic acid model of autism

“…At present, the clinical treatment of autism remains a big challenge. Researchers have demonstrated that a ketogenic diet (KD) plays a potential therapeutic role and may attenuate social and metabolic alterations identified in the VPA model of autism (34). Furthermore, the treatment effect of the KD may be caused by a reduction in the activity of AMPK/ACC pathway and heat shock protein 70 to decrease kainic acid-induced hippocampal cell death (35).…”