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.

Keywords:
Play behavior, Mitochondria, Autism, Valproic acid, Metabolism, Respiration
1.
Mefford HC, Batshaw ML, Hoffman, EP: Genomics, intellectual disability, and autism. N Engl J Med 2012;366:733-743.
2.
Haas R: Autism and mitochondrial disease. Dev Disabil Res Rev 2010;16:144-153.
3.
Veenstra-Vander Weele J, Blakely RD: Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology 2012;37:196-212.
4.
Persico AM, Bourgeron T: Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006;29:349-358.
5.
Rinaldi T, Kulangara K, Antoniello K, Markram H: Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci USA 2007;104:13501-13506.
6.
Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH: Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001;43:202-206.
7.
Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC: Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 2005;47: 551-555.
8.
Christensen J, Koops Gronborg T, Juul Sorensen M, Schendel D, Thorlund Parner E, Henning Pedersen L, Vestergaard M: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013;309:1696-1703.
9.
Arndt TL, Stodgell CJ, Rodier PM: The teratology of autism. Int J Dev Neurosci 2005;23:189-199.
10.
Schneider T, Przewlocki R: Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005;30:80-89.
11.
Ingram J, Peckham S, Tisdale B, Rodier P: Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 2000;22:319-324.
12.
Rodier P: Animal model of autism based on developmental data. Ment Retard Dev Disabil Res Rev 1996;2:249-256.
13.
Mychasiuk R, Richards S, Nakahashi A, Kolb B, Gibb R: Effects of prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci 2012;34:268-276.
14.
Chomiak T, Turner N, Hu B: What we have learned about autism spectrum disorder from valproic acid. Patholog Res Int 2013;2013: 712758.
15.
Rossignol D, Frye R: Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 2012;17:290-314.
16.
Masino S, Rho J: Mechanisms of ketogenic diet action; in J. Noebels, M. Avoli, M. Rogawski (eds): Jasper's Basic Mechanisms of the Epilepsies. Bethesda, National Center for Biotechnology Information, 2012.
17.
Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene J, Shaw R, Smith Y, Geiger J, Dingledine RJ: Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006;60:223-235.
18.
Wilder RM: The effects of ketonemia on the course of epilepsy. Mayo Clin Proc 1921;2:2.
19.
McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M: The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 2011;52:e7-e11.
20.
Wheless JW: The ketogenic diet: fa(c)t or fiction. J Child Neurol 1995;10:419-423.
21.
Nordli DR Jr, De Vivo DC: The ketogenic diet revisited: back to the future. Epilepsia 1997;38:743-749.
22.
Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, Shinnar S, Shuman R, Trevathan E, Wheless JW: A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55:1433-1437.
23.
Kim do Y, Davis LM, Sullivan PG, Maalouf M, Simeone TA, van Brederode J, Rho J: Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 2007;101:1316-1326.
24.
Kim do Y, Hao J, Liu R, Turner G, Shi FD, Rho J: Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One 2012;7:e35476.
25.
Haas RH, Rice MA, Trauner DA, Merritt TA: Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet Suppl 1986;1:225-246.
26.
Liebhaber GM, Riemann E, Baumeister FA: Ketogenic diet in Rett syndrome. J Child Neurol 2003;18:74-75.
27.
Bujas-Petkovic Z, Matijasic R, Divcic B: Rett's syndrome - differential diagnosis of autism in a case report. Lijec Vjesn 1989;111:458-460.
28.
Chahrour M, Zoghbi HY: The story of Rett syndrome: from clinic to neurobiology. Neuron 2007;56:422-437.
29.
Francke U: Mechanisms of disease: neurogenetics of MeCP2 deficiency. Nat Clin Pract Neurol 2006;2:212-221.
30.
LaSalle JM, Yasui DH: Evolving role of MeCP2 in Rett syndrome and autism. Epigenomics 2009;1:119-130.
31.
Evangeliou A, Vlachonikolis I, Mihailidou H, Spilioti M, Skarpalezou A, Makaronas N, Prokopiou A, Christodoulou P, Liapi-Adamidou G, Helidonis E, Sbyrakis S, Smeitink J: Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol 2003;18:113-118.
32.
Williams E, Reddy V, Costall A: Taking a closer look at functional play in children with autism. J Autism Dev Disord 2001;31:67-77.
33.
Bell H, Pellis S, Kolb B: Juvenile peer play experience and the development of the orbitofrontal and medial prefrontal cortices. Behav Brain Res 2010;207:7-13.
34.
Pellis S, Pellis V: Rough and tumble play and the development of the social brain. Curr Dir Psychol Sci 2007;16:95-98.
35.
Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T: Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 2013;16:91-103.
36.
Chomiak T, Karnik V, Block E, Hu B: Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism. BMC Neurosci 2010;11:102.
37.
Fenoglio-Simeone KA, Wilke JC, Milligan HL, Allen CN, Rho, JM, Maganti RK: Ketogenic diet treatment abolishes seizure periodicity and improves diurnal rhythmicity in epileptic Kcna1-null mice. Epilepsia 2009;50:2027-2034.
38.
Pellis SM, Pellis VC: Play fighting of rats in comparative perspective: a schema for neurobehavioral analyses. Neurosci Biobehav Rev 1998;23:87-101.
39.
Pellis S, Pellis V: Differential rates of attack, defense and counterattack during development decrease in play fighting by male and female rats. Dev Psychobiol 1990;23:215-231.
40.
Sullivan P, Dube C, Dorenbos K, Oswald S, Baram T: Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol 2003;53:711-717.
41.
Sullivan P, Rippy N, Dorenbos K, Concepcion R, Agarwal A, Rho J: The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004;55:576-580.
42.
Pandya J, Pauly J, Sullivan P: The optimal dosage and window of opportunity to maintain mitochondrial homeostasis following traumatic brain injury using the uncoupler FCCP. Exp Neurol 2009;218:381-389.
43.
Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, Morgan J: Mapping early brain development in autism. Neuron 2007;56:399-413.
44.
Schumann CM, Bloss CS, Barnes CC, Wideman GM, Carper RA, Akshoomoff N, Pierce K, Hagler D, Schork N, Lord C, Courchesne E: Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism. J Neurosci 2010;30:4419-4427.
45.
Pellis S, Pellis V, Bell H: The function of play in the development of the social brain. Am J Play 2010;2:278-296.
46.
Hol T, Van den Berg M, Van Ree J, Spruijt B: Isolation during the play period in infancy decreases adult social interactions in rats. Behav Brain Res 1999;100:91-97.
47.
Parihar M, Brewer G: Mitoenergetic failure in Alzheimer disease. Am J Physiol 2007;292: C8-C23.
48.
Brand M, Nichols D: Assessing mitochondrial dysfunction in cells. Biochem J 2001;435:297-312.
49.
Stafstrom CE, Rho JM: The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 2012;3:59.
50.
Morris A: Cerebral ketone body metabolism. J Inherit Metab Dis 2005;28:109-121.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.