Andrew McCarthy

Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia.

Summary Rhythmic neural network activity patterns are defining features of sleep, but interdependencies between limbic and cortical oscillations at different frequencies and their functional roles have not been fully resolved. This is particularly important given evidence linking abnormal sleep architecture and memory consolidation in psychiatric diseases. Using EEG, local field potential (LFP), and unit recordings in rats, we show that anteroposterior propagation of neocortical slow-waves coordinates timing of hippocampal ripples and prefrontal cortical spindles during NREM sleep. This coordination is selectively disrupted in a rat neurodevelopmental model of schizophrenia: fragmented NREM sleep and impaired slow-wave propagation in the model culminate in deficient ripple-spindle coordination and disrupted spike timing, potentially as a consequence of interneuronal abnormalities reflected by reduced parvalbumin expression. These data further define the interrelationships among slow-wave, spindle, and ripple events, indicating that sleep disturbances may be associated with state-dependent decoupling of hippocampal and cortical circuits in psychiatric diseases.

Differential effects of NMDA antagonists on high frequency and gamma EEG oscillations in a neurodevelopmental model of schizophrenia

Neuroanatomical, electrophysiological and behavioural abnormalities following timed prenatal methylazoxymethanol acetate (MAM) treatment in rats model changes observed in schizophrenia. In particular, MAM treatment on gestational day 17 (E17) preferentially disrupts limbic-cortical circuits, and is a promising animal model of schizophrenia. The hypersensitivity of this model to the NMDA receptor antagonist-induced hyperactivity has been proposed to mimic the increase in sensitivity observed in schizophrenia patients following PCP and Ketamine administration. However, how this increase in sensitivity in both patients and animals translates to differences in EEG oscillatory activity is unknown. In this study we have shown that MAM-E17 treated animals have an increased response to the hyperlocomotor and wake promoting effects of Ketamine, PCP, and MK801 but not to the competitive antagonist SDZ 220,581. These behavioural changes were accompanied by altered EEG responses to the NMDAR antagonists, most evident in the gamma and high frequency (HFO) ranges; altered sensitivity of these neuronal network oscillations in MAM-exposed rats is regionally selective, and reflects altered interneuronal function in this neurodevelopmental model.

Electroencephalographic, cognitive, and neurochemical effects of LY3130481 (CERC-611), a selective antagonist of TARP-γ8-associated AMPA receptors

&NA; 6‐[(1S)‐1‐[1‐[5‐(2‐hydroxyethoxy)‐2‐pyridyl]pyrazol‐3‐yl]ethyl]‐3H‐1,3‐benzothiazol‐2‐one (LY3130481 or CERC‐611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) &ggr;−8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food‐maintained responding in rats and spontaneous alternation in a Y‐maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal‐dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive‐impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor‐impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non‐rapid‐eye movement sleep induced by carbamazepine. Evaluation of the effect of LY3130481 on neurotransmitter and metabolite efflux in the rat medial prefrontal cortex, using in vivo microdialysis, revealed significant increases in the pro‐cognitive and wake‐promoting neurotransmitters, histamine and acetylcholine, as well as in serotonin, telemethylhistamine, 5‐HIAA, HVA and MHPG. LY3130481 thus presents a novel behavioral profile that will have to be evaluated in patients to fully appreciate its implications for therapeutics. LY3130481 is currently under clinical development as CERC‐611 as an antiepileptic. HighlightsLY3130481 (CERC‐611) is a selective antagonist of AMPA receptors TARP &ggr;−8 protein.LY3130481 is currently under clinical development as CERC‐611 as an antiepileptic.LY3130481 produced mixed results in rodent cognition assessments.LY3130481 produced modest increases in wake times in rats and increased wake and cognition‐associated neurotransmitters.LY3130481 attenuated some impairing effects of standard antiepileptic drugs.

Modelling maintenance of wakefulness in rats: comparing potential non-invasive sleep-restriction methods and their effects on sleep and attentional performance.

While several methods have been used to restrict the sleep of experimental animals, it is often unclear whether these different forms of sleep restriction have comparable effects on sleep–wake architecture or functional capacity. The present study compared four models of sleep restriction, using enforced wakefulness by rotation of cylindrical home cages over 11 h in male Wistar rats. These included an electroencephalographic‐driven ‘Biofeedback’ method and three non‐invasive methods where rotation was triggered according to a ‘Constant’, ‘Decreasing’ or random protocol based upon the ‘Weibull’ distribution fit to an archival Biofeedback dataset. Sleep–wake architecture was determined using polysomnography, and functional capacity was assessed immediately post‐restriction with a simple response latency task, as a potential homologue of the human psychomotor vigilance task. All sleep restriction protocols resulted in sleep loss, behavioural task disengagement and rebound sleep, although no model was as effective as real‐time electroencephalographic‐Biofeedback. Decreasing and Weibull protocols produced greater recovery sleep than the Constant protocol, mirrored by comparably poorer simple response latency task performance. Increases in urinary corticosterone levels following Constant and Decreasing protocols suggested that stress levels may differ between protocols. Overall, these results provide insight into the value of choosing a specific sleep restriction protocol, not only from the perspective of animal welfare and the use of less invasive procedures, but also translational validity. A more considered choice of the physiological and functional effects of sleep‐restriction protocols in rodents may improve correspondence with specific types of excessive daytime sleepiness in humans.

Investigating the role of mGluR2 versus mGluR3 in antipsychotic-like effects, sleep-wake architecture and network oscillatory activity using novel Han Wistar rats lacking mGluR2 expression

Abstract Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep‐wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands. The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine‐ and phencyclidine‐induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose‐dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake‐promoting effects in both rat strains, albeit smaller in the mGluR2‐lacking Han Wistar rats, indicating both mGluR2 and mGluR3‐mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4–9 Hz) and gamma (30–80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats. Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic‐like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations.