Elsevier

Schizophrenia Research

Volume 193, March 2018, Pages 119-125
Schizophrenia Research

Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia

https://doi.org/10.1016/j.schres.2017.06.027Get rights and content

Abstract

Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia.

Introduction

Cognitive deficits strongly predict long-term functional disability in schizophrenia, but existing standard-of-care antipsychotic medications lack efficacy for improving cognition and functional outcomes in patients (Corigliano et al., 2014, Eastvold et al., 2007, Green, 1996, Green et al., 2004, Jahshan et al., 2010, Nuechterlein et al., 2014). Disturbance in the balance of neural excitation and inhibition (E/I) is recognized as possibly contributing to both psychotic and cognitive dysfunctions in schizophrenia (Foss-Feig et al., 2017, Krystal et al., 2017). For example, recent evidence from human neuroimaging studies points to heightened neural activity localized to the medial temporal lobe as a potential driver of pathophysiology in schizophrenia, exerting significant adverse effects on cognitive function (Medoff et al., 2001, Sanderson et al., 2012, Schobel et al., 2009, Schobel et al., 2013, Tregellas et al., 2014, Zierhut et al., 2010). Specifically, the level of neural hyperactivity correlates with worse cognitive performance in patients (Tregellas et al., 2014), and the hyperactivity in a prodromal phase of illness predicts clinical progression to overt psychosis within two years (Schobel et al., 2009).

Preclinical animal models of schizophrenia have recapitulated key neurobehavioral features of the disease, including E/I imbalance in the neural circuits important for cognitive function. For example, higher metabolic basal activity and neuronal firing rates have been observed in adult animals exposed prenatally to the antimitotic compound methylazoxymethanol acetate or to the NMDA receptor antagonist ketamine during adolescence (Gill et al., 2011, Lodge and Grace, 2007, Schobel et al., 2013). Importantly, those same pharmacological induction protocols that produce changes in neural activity lead to cognitive dysfunction detected by behavioral assessments (Koh et al., 2016, Moore et al., 2006). In vitro slice recordings from such treated animals have also provided evidence for neuronal hyperactivity of principal neurons in the hippocampus that are partially normalized by diazepam administration (Sanderson et al., 2012). Thus, both preclinical and clinical data suggest that increased neural activity is a condition contributing to dysfunction in this illness.

We set out to investigate whether targeting neural overactivity with levetiracetam, an atypical antiepileptic agent that binds with high affinity to the synaptic vesicle 2A (SV2A) protein to regulate synaptic exocytosis and neurotransmitter release, would be effective at improving cognition in an animal model of schizophrenia that has been shown to exhibit heightened neural activity. Levetiracetam has already been evaluated in an animal model of impaired sensory gating, and was found to improve auditory gating in mice with schizophrenia-like gating deficits (Smucny et al., 2015). Low dose treatment with levetiracetam has also been found to improve memory in aging and Alzheimer's disease that are associated with increased neural activity in the medial temporal lobe (Devi and Ohno, 2013, Hall et al., 2015, Koh et al., 2010, Sanchez et al., 2012, Suberbielle et al., 2013). Taken together, the beneficial effects of levetiracetam on normalizing neural overactivity suggests that reduction in neural overactivity by levetiracetam may have potential efficacy on cognition in schizophrenia.

In the present studies, we assessed the ability of levetiracetam to alleviate memory impairment in a ketamine animal model of schizophrenia that recapitulates neural hyperactivity and memory problems akin to those seen in schizophrenia patients (Koh et al., 2016, Olney et al., 1999, Neill et al., 2010, Schobel et al., 2013). We tested levetiracetam, alongside and in combination with the antipsychotic medication, risperidone, to compare their efficacy to improve cognition under the same testing conditions. We further examined whether levetiracetam alleviates the augmented response to a dopamine agonist amphetamine, a commonly used behavioral assay to assess a dopaminergic perturbation that is central to the illness. Levetiracetam, but not risperidone, was found to improve memory performance dose-dependently in a hippocampal-dependent memory task, and levetiracetam remained effective when administered concurrently with antipsychotic drug treatment. In addition, levetiracetam attenuated the response to amphetamine in the ketamine model, also suggesting a potential link between hippocampal overactivity and dopamine system dysfunction as proposed by other investigators (Grace, 2012, Lodge and Grace, 2007).

Section snippets

Subjects

Male Long-Evans rats were obtained at approximately 5 weeks old from Charles River Laboratories (Raleigh, NC), and housed individually at 25 °C and maintained on a 12-h light/dark cycle. Food (Purina autoclave laboratory rodent diet) and water were provided ad libitum unless otherwise noted. All procedures in the current investigations were approved by the Institutional Animal Care and Committee in accordance with the National Institutes of Health directive.

Ketamine exposure

Ketamine (VedCo; 100 mg/ml

Ketamine exposure impaired memory performance

We first examined whether rats exposed to ketamine subchronically during late adolescence/early adulthood showed memory impairment as has been reported elsewhere (e.g., Enomoto and Floresco, 2009, Olney et al., 1999, Neill et al., 2010). We used a well-established radial arm maze task to assess cognitive performance that is known to be dependent on the hippocampal memory system (e.g., Olton et al., 1982, Schlesiger et al., 2013), and also allowed for within-subject assessment of different drug

Discussion

Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Administration of subchronic ketamine to rodents induces a condition of increased neural activity that is localized to the hippocampus (Schobel et al., 2013). Low doses of the atypical antiepileptic agent levetiracetam aimed at reducing increased neural activity were effective at alleviating cognitive impairment. The antipsychotic medication risperidone in contrast was

Contributors

MTK, SRL, and MG developed the study design, MTK and YS performed the experiments, and all authors contributed to and approved the final manuscript.

Role of funding agencies

None of the funding agencies had a role in collection, management, analysis or interpretation of the data or in preparation, review or approval of the manuscript.

Conflict of interest

MG is the founder of AgeneBio Incorporated, a biotechnology company that is dedicated to discovery and development of therapies to treat cognitive impairment in aging. She has a financial interest in the company. Her conflict of interest is managed by Johns Hopkins University. MTK and MG are inventors on Johns Hopkins University intellectual property licensed to AgeneBio. MTK and YS have received no financial support or compensation from any individual or corporate entity for research or

Acknowledgements

This research was supported by the Silvo O. Conte Center, P50MH094268. YS was a Woodrow Wilson Fellow at Johns Hopkins University.

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