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. 2013 Jun 5;8(6):e65021.
doi: 10.1371/journal.pone.0065021. Print 2013.

Ketogenic Diet Improves Core Symptoms of Autism in BTBR Mice

Free PMC article

Ketogenic Diet Improves Core Symptoms of Autism in BTBR Mice

David N Ruskin et al. PLoS One. .
Free PMC article


Autism spectrum disorders share three core symptoms: impaired sociability, repetitive behaviors and communication deficits. Incidence is rising, and current treatments are inadequate. Seizures are a common comorbidity, and since the 1920's a high-fat, low-carbohydrate ketogenic diet has been used to treat epilepsy. Evidence suggests the ketogenic diet and analogous metabolic approaches may benefit diverse neurological disorders. Here we show that a ketogenic diet improves autistic behaviors in the BTBR mouse. Juvenile BTBR mice were fed standard or ketogenic diet for three weeks and tested for sociability, self-directed repetitive behavior, and communication. In separate experiments, spontaneous intrahippocampal EEGs and tests of seizure susceptibility (6 Hz corneal stimulation, flurothyl, SKF83822, pentylenetetrazole) were compared between BTBR and control (C57Bl/6) mice. Ketogenic diet-fed BTBR mice showed increased sociability in a three-chamber test, decreased self-directed repetitive behavior, and improved social communication of a food preference. Although seizures are a common comorbidity with autism, BTBR mice fed a standard diet exhibit neither spontaneous seizures nor abnormal EEG, and have increased seizure susceptibility in just one of four tests. Thus, behavioral improvements are dissociable from any antiseizure effect. Our results suggest that a ketogenic diet improves multiple autistic behaviors in the BTBR mouse model. Therefore, ketogenic diets or analogous metabolic strategies may offer novel opportunities to improve core behavioral symptoms of autism spectrum disorders.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. A KD reduces symptoms of autism in BTBR mice.
(A) KD increases social interactions in the three-chamber test of sociability. During phase 2, CD-fed mice did not spend significantly more time with a mouse-containing versus an empty chamber (middle). However, KD-fed mice preferred spending time in the chamber with a mouse (middle). During phase 3, diet did not affect preference for social novelty (right). Diet F(1,112) = 8.9, p<0.01; Social situation F(2,112) = 12.5, p<0.001; Diet-by-Social situation interaction F(2,112) = 3.2, p<0.05; n = 28–30. (B) KD feeding increases sociability as assessed in phase 3 of (A). Although there was no diet-related preference for social novelty, there was a significant diet-related difference in total time spent in frontal contact with the small wire cages, both of which contained mice. KD-fed mice spent significantly more time in frontal contact. n = 28–30. (C) KD feeding had no effect during phase 1, but resulted in significantly less self-directed repetitive behavior in phases 2 and 3 as assessed by time spent grooming. Diet F(1,111) = 22.1, p<0.001; Phase F(2,111) = 17.1, p<0.001; Diet-by-Phase interaction F(2,111) = 6.8, p<0.01; n = 28–30. (D) KD feeding improves communication as assessed by the transmission of a food preference through social interaction; KD-fed mice ate significantly more of the trained flavor. Diet F(1,33) = 42.5, p<0.001; Flavor F(1,33) = 2.6, n.s.; Diet-by-Flavor interaction F(1,33) = 6.8, p<0.05; n = 17–18. ***p<0.001, CD v. KD; §§p<0.01, §§§p<0.001 v. baseline (phase 1).
Figure 2
Figure 2. BTBR mice have normal electrical brain activity comparable to control mice.
Cortical and intrahippocampal CA3 EEG traces from BTBR (right panels) and control C57Bl/6 (left panels) mice (n = 4/strain) recorded continuously for 72 h. Upper traces within each brain region are representative recordings of a 1 min period; lower traces are a higher resolution excerpt of the first 4 s from the respective upper trace. Throughout the 72 h recording period there was no evidence of electrographic seizures or any other pathological brain activity as determined by comparing the spike pattern, amplitude and frequency between the BTBR and C57Bl/6 EEGs.
Figure 3
Figure 3. BTBR mice exhibit a varied seizure phenotype.
(A) In response to 6 Hz electroconvulsive shocks, BTBR mice had a significantly reduced threshold compared to control mice, and this reduction was unaffected by KD feeding. *p<0.05 compared to control; n = 16 CD group, n = 8 KD group. (B) BTBR mice did not differ from control mice in latency to tonic/clonic seizures during flurothyl exposure; n = 7–8. (C) Peak seizure intensity was not different between BTBR and control mice in response to PTZ injection; n = 10–12. (D) Latency to first seizure after injection of the dopamine agonist SKF83822 was reduced in BTBRs, but the number of seizures did not differ. **p<0.01 compared to controls; n = 9–13.

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