Metabolic dysfunction can underlie seizure disorders, and metabolism-based treatments can afford seizure control and promote homeostasis. This relationship between metabolism and the risk of sporadic seizures was observed historically with the clinical success of a low-carbohydrate, high-fat, ketosis-inducing ketogenic diet - a treatment that remains relevant today, and one that has been shown to be effective against medically refractory epilepsy. Mechanisms underlying the success of the ketogenic diet are a topic of intense research efforts - not only because of proven success in arresting treatment-resistant seizures, but also because recent evidence suggests that altering metabolism with a ketogenic diet enables a homeostatic state in the brain that is less excitable, and hence raises the threshold for seizure genesis. Metabolic therapy with a ketogenic diet has been shown to normalize a range of abnormal physiological and behavioral parameters and may also make the central nervous system more resilient to other insults or physiological stresses. Because the therapeutic ability of such a diet may be more limited than a drug because of a dose "ceiling", investigations are underway to develop and test analogous or supplemental approaches. In addition, significant efforts have been made to demonstrate broader applications of metabolic therapy in promoting health and preventing disease, including conditions where epileptic seizures manifest in a comorbid fashion.

Autism spectrum disorder (ASD) is characterized by deficits in sociability and communication, and increased repetitive and/or restrictive behaviors. While the etio-pathogenesis of ASD is unknown, clinical manifestations are diverse and many possible genetic and environmental factors have been implicated. As such, it has been a great challenge to identify key neurobiological mechanisms and to develop effective treatments. Current therapies focus on co-morbid conditions (such as epileptic seizures and sleep disturbances) and there is no cure for the core symptoms. Recent studies have increasingly implicated mitochondrial dysfunction in ASD. The fact that mitochondria are an integral part of diverse cellular functions and are susceptible to many insults could explain how a wide range of factors can contribute to a consistent behavioral phenotype in ASD. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), used for nearly a century to treat medically intractable epilepsy, has been shown to enhance mitochondrial function through a multiplicity of mechanisms and affect additional molecular targets that may address symptoms and comorbidities of ASD. Here, we review the evidence for the use of metabolism-based therapies such as the KD in the treatment of ASD as well as emerging co-morbid models of epilepsy and autism. Future research directions aimed at validating such therapeutic approaches and identifying additional and novel mechanistic targets are also discussed.

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental disorder characterized by decreased reciprocal social interaction, abnormal communication, and repetitive behaviors with restricted interest. As diagnosis is based on clinical criteria, any potentially relevant rodent models of this heterogeneous disorder should ideally recapitulate these diverse behavioral traits. The BTBR T+ Itpr3tf/J (BTBR) mouse is an established animal model of ASD, displaying repetitive behaviors such as increased grooming, as well as cognitive inflexibility. With respect to social interaction and interest, the juvenile play test has been employed in multiple rodent models of ASD. Here, we show that when BTBR mice are tested in a juvenile social interaction enclosure containing sawdust bedding, they display a repetitive synchronous digging motion. This repetitive motor behavior, referred to as "inchworming," was named because of the stereotypic nature of the movements exhibited by the mice while moving horizontally across the floor. Inchworming mice must use their fore- and hind-limbs in synchrony to displace the bedding, performing a minimum of one inward and one outward motion. Although both BTBR and C56BL/6J (B6) mice exhibit this behavior, BTBR mice demonstrate a significantly higher duration and frequency of inchworming and a decreased latency to initiate inchworming when placed in a bedded enclosure. We conclude that this newly described behavior provides a measure of a repetitive motor stereotypy that can be easily measured in animal models of ASD.