Ketogenic diet and olanzapine treatment alone and in combination reduce a pharmacologically-induced prepulse inhibition deficit in female mice
Introduction
Clinical evidence suggests a metabolic involvement in the pathophysiology of schizophrenia (Fujimoto et al., 2007; Beasley et al., 2009; Harris et al., 2013; Sullivan et al., 2018; Sullivan et al., 2019). For example, impaired pyruvate and adenosine-triphosphate (ATP) production was found in the cortex of schizophrenia patients in vivo (Du et al., 2014) and in post-mortem samples of the medial dorsal thalamus (Martins-de-Souza et al., 2010). These changes result in decreased energy availability for the brain and may lead to impaired neuronal functioning (Arnaiz et al., 2001; Lamport et al., 2009). Post-mortem studies of the thalamus and dorsolateral prefrontal cortex of schizophrenia patients suggested that glycolysis was the main pathway impaired (Martins-de-Souza et al., 2010; Sullivan et al., 2018). We hypothesised that a ketogenic diet may provide an alternative fuel source to glucose by causing a metabolic shift to fatty acid utilisation (Paoli et al., 2013). We recently reported in an acute N-methyl-d-aspartate (NMDA) receptor hypofunction model in male mice, that a ketogenic diet exerts antipsychotic-like effects (Kraeuter et al., 2015; Kraeuter et al., 2019), suggesting that it may provide an adjunct therapy to commonly used antipsychotics. Indeed, recent clinical case studies have shown encouraging results with ketogenic diet being used as an adjunct therapy (Palmer, 2017; Gilbert-Jaramillo et al., 2018; Palmer et al., 2019; Sarnyai et al., 2019). However, in the clinical setting this dietary intervention would presumably be administered together with antipsychotic treatment over an extended period of time. Therefore, the interaction between long-term ketogenic diet and antipsychotic administration remains to be investigated.
Our previous studies have only investigated the effects of ketogenic diet in male mice. Recent studies in mice have shown sex differences in the behavioural and metabolic effects of ketogenic diet (Ruskin et al., 2017a, Ruskin et al., 2017b, Cochran et al., 2018). For example, in a mouse model of Autism Spectrum Disorder, ketogenic diet improved multiple measures of sociability and reduced repetitive behaviour in female mice, but there were limited effects in males (Ruskin et al., 2017a, Ruskin et al., 2017b). In contrast, in a maternal immune activation model, ketogenic diet prevented these behaviours in males, but not females (Ruskin et al., 2017a, Ruskin et al., 2017b). Therefore, to compare to our previous studies in male mice, the present study was conducted in female mice.
In this study we used acute disruption of prepulse inhibition (PPI) by the NMDA receptor antagonist, MK-801. Information processing deficits are a clinical manifestation of schizophrenia (Braff et al., 2001). PPI is a measure of sensorimotor gating and is highly translatable between rodents and humans (van den Buuse, 2010, Swerdlow and Light, 2018). Here, (1) we investigate the efficacy of the ketogenic diet in female mice, (2) to compare it to a commonly used antipsychotic, olanzapine, and (3) to explore the interaction between these treatments.
Section snippets
Methods
The experiments were approved by the Animal Ethics Committee of James Cook University (A2036) and were conducted according to the NHMRC/AVCC Statement and Guidelines on Research Practice (1997). Female C57/BL6 mice (n = 52) of 7 weeks of age were obtained from the James Cook University breeding facility and kept on a 12 h light/dark cycle with ad libitum access to food and water. All experiments were done during the light phase.
At commencement of the study, mice were randomly allocated to
Results
Similar to our previous results (Kraeuter et al., 2015; Kraeuter et al., 2019), there was an initial reduction of weight gain in mice on a ketogenic diet, leading to lower body weights in these animals compared to standard-diet controls for about four weeks. However, by the time behavioural testing was done, there were no differences in body weight between the groups. There were no differences in weight gain in animals treated with olanzapine alone or the combination with ketogenic diet (data
Discussion
We previously demonstrated in male mice the efficacy of ketogenic diet on a variety of behavioural changes by normalising hyperactivity, stereotypic behaviour, social behaviour, working memory (Kraeuter et al., 2015) and pre-pulse inhibition of startle (Kraeuter et al., 2019) in an acute NMDA receptor hypofunction model. In the present study, we found that the beneficial effects of ketogenic diet on MK-801-induced disruption of PPI could be generalised to female mice. Furthermore, comparison of
Contributors
AKK and ZS conceived the idea and designed the study. AKK carried out the behavioural studies, analysed the data and wrote the first draft of the manuscript. Nadia Archambault (NA) assisted with data collection. ZS and MvdB analysed some of the data and edited the draft to the final version. All authors contributed to and have approved the final manuscript.
Declaration of competing interest
The authors have no conflict of interest to report.
Acknowledgement
This study was supported by an internal grant from James Cook University to Zoltan Sarnyai (ZS). Ann-Katrin Kraeuter (AKK) was supported by a James Cook University (JCU) Postgraduate Research Scholarship and a Higher Degree Research Enhancement Scheme from JCU. Maarten van den Buuse (MvdB) was supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.
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