Effects of the mGlu2/3 receptor agonist LY379268 on two models of disturbed auditory evoked brain oscillations in mice

Abstract

Cognitive impairment is a core feature of schizophrenia and is poorly addressed by currently available medication. This is partly because the underlying circuits are insufficiently understood, and available animal models for brain dysfunction do not adequately mimic human pathology. To improve the translatability of animal studies and complement behavioral data, EEG measurements are being increasingly used in preclinical research. Brain oscillations are similar across species and can be impaired via several means. In this study, we used two approaches to impair early sensory processing and cortical oscillations in mice: a pharmacological model targeting NMDA receptor function in the whole brain via systemic MK-801 application and an optogenetic model targeting parvalbumin-positive (PV+) interneurons locally in the medial prefrontal cortex (mPFC). We evoked brain activity using auditory stimulation, a tool with high translatability from mouse to human. We then investigated the effect of LY379268, an agonist of mGlu2/3 receptors, a potential therapeutic target for schizophrenia, on single neuron and EEG responses. LY379268 was able to rescue MK-801-induced deficits for a variety of clinically relevant early sensory EEG biomarkers. Single neuron recordings revealed a strong effect of LY379268 on the signal-to-noise ratio during auditory stimulation and optogenetic inhibition of PV+ interneurons. Our results contribute to a better understanding of how group II metabotropic glutamate receptors modulate neuronal population and network activity under sensory stimulation while challenged pharmacologically or optogenetically.