Influencing cognitive performance via social interactions: a novel therapeutic approach for brain disorders based on neuroanatomical mapping?

Many psychiatric and neurological disorders present deficits in both the social and cognitive domain. In this perspectives article, we provide an overview and the potential of the existence of an extensive neurobiological substrate underlying the close relationship between these two domains. By mapping the rodent brain regions involved in the social and/or cognitive domain, we show that the vast majority of brain regions involved in the cognitive domain are also involved in the social domain. The identified neuroanatomical overlap has an evolutionary basis, as complex social behavior requires cognitive skills, and aligns with the reported functional interactions of processes underlying cognitive and social performance. Based on the neuroanatomical mapping, recent (pre-)clinical findings, and the evolutionary perspective, we emphasize that the social domain requires more focus as an important treatment target and/or biomarker, especially considering the presently limited treatment strategies for these disorders.

Recommendations for Preclinical Testing of Treatments Against Alzheimer's Disease-Related Epileptiform Spikes in Transgenic Rodent Models.

Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer's disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models. Transgenic rodent models of AD pathology exhibit various forms of epileptiform EEG activity related to the abnormal levels of amyloid species in the brain. Among them, large-amplitude cortical and hippocampal EEG spikes in mouse and rat AD models may be reminiscent of the subclinical epileptiform EEG spikes recorded in some AD patients. This article reports the recommendations of a multidisciplinary panel of experts on optimal EEG markers and experimental designs to measure and report epileptiform activities and their response to symptomatic and disease-modifying drugs in transgenic AD model rodents. These recommendations may harmonize future preclinical EEG studies in the drug discovery research and may increase the comparability of experimental outcomes and their translational clinical value.

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats.

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.

Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study.

The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer's disease (AD) patients, and age-matched healthy controls. To evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease evaluation of the MMN response. Our findings suggest further investigations to support the identification of neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and clinical stages of SZ drug development.

Odour Retrieval Processing in Mice: Cholinergic Modulation of Oscillatory Coupling in Olfactory Bulb-Piriform Networks.

BACKGROUND/AIMS: Olfactory dysfunction can provide valuable insight into early pathophysiological processes of brain disorders. Olfactory processing of chemosensory and odour sensitivity relies on segregating salient odours from background odours cues. Odour-evoked fast oscillations in the olfactory bulb (OB) are hypothesized to be an important index of odour quality coding. The present preclinical work aimed at better understanding connectivity associated with odour coding and behavioural odour discrimination. METHODS: Network oscillations and functional connectivity (FC) were measured in C57BL/6 mice performing the olfactory associative odour learning (OL) test, using multichannel local field potential recordings in key olfactory networks. Cholinergic modulation of odour processing was investigated using the muscarinic antagonist scopolamine. RESULTS: At the behavioural level, olfactory memory, which refers to the acquisition and recollection of a reference odour by reduced exploration time, was observed in animals that correctly learned the task. Significant decrease in mean investigation and retrieval time of the associated odour-food reward was observed between trials. At the network level, the associated odour during sniffing behaviour was associated with enhanced coherence in the ß and γ frequency oscillations across the olfactory pathway, with marked changes observed between the OB and anterior piriform cortex (PC). The enhanced phase-amplitude cross-frequency coupling in the OB and the weak coupling index in the hippocampal CA1 suggests a role of the OB network in olfaction encoding and processing. Scopolamine impaired behavioural and FC underlying recall and retrieval of the associated odour. CONCLUSION: The results suggest that the acquisition and formation of odour reference memory rely primarily on FC at the OB-PC network and confirm the role of muscarinic receptors in olfactory retrieval processing.

Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study.

OBJECTIVE: In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid ß-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer's disease (AD) amyloid neuropathology as compared to wild type (WT) mice. METHODS: Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. RESULTS: Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). CONCLUSIONS: The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.

Functional Alterations in the Olfactory Neuronal Circuit Occur before Hippocampal Plasticity Deficits in the P301S Mouse Model of Tauopathy: Implications for Early Diagnosis and Translational Research in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by neuronal loss and impaired synaptic transmission, ultimately leading to cognitive deficits. Early in the disease, the olfactory track seems most sensitive to tauopathy, while most plasticity studies focused on the hippocampal circuits. Functional network connectivity (FC) and long-term potentiation (LTP), considered as the plasticity substrate of learning and memory, were longitudinally assessed in mice of the P301S model of tauopathy following the course (time and location) of progressively neurodegenerative pathology (i.e., at 3, 6, and 9 months of age) and in their wild type (WT) littermates. Using in vivo local field potential (LFP) recordings, early (at three months) dampening in the gamma oscillatory activity and impairments in the phase-amplitude theta-gamma coupling (PAC) were found in the olfactory bulb (OB) circuit of P301S mice, which were maintained through the whole course of pathology development. In contrast, LFP oscillatory activity and PAC indices were normal in the entorhinal cortex, hippocampal CA1 and CA3 nuclei. Field excitatory postsynaptic potential (fEPSP) recordings from the Shaffer collateral (SC)-CA1 hippocampal stratum pyramidal revealed a significant altered synaptic LTP response to high-frequency stimulation (HFS): at three months of age, no significant difference between genotypes was found in basal synaptic activity, while signs of a deficit in short term plasticity were revealed by alterations in the fEPSPs. At six months of age, a slight deviance was found in basal synaptic activity and significant differences were observed in the LTP response. The alterations in network oscillations at the OB level and impairments in the functioning of the SC-CA1 pyramidal synapses strongly suggest that the progression of tau pathology elicited a brain area, activity-dependent disturbance in functional synaptic transmission. These findings point to early major alterations of neuronal activity in the OB circuit prior to the disturbance of hippocampal synaptic plasticity, possibly involving tauopathy in the anomalous FC. Further research should determine whether those early deficits in the OB network oscillations and FC are possible mechanisms that potentially promote the emergence of hippocampal synaptic impairments during the progression of tauopathy.

International Federation of Clinical Neurophysiology (IFCN) - EEG research workgroup: Recommendations on frequency and topographic analysis of resting state EEG rhythms. Part 1: Applications in clinical research studies.

In 1999, the International Federation of Clinical Neurophysiology (IFCN) published "IFCN Guidelines for topographic and frequency analysis of EEGs and EPs" (Nuwer et al., 1999). Here a Workgroup of IFCN experts presents unanimous recommendations on the following procedures relevant for the topographic and frequency analysis of resting state EEGs (rsEEGs) in clinical research defined as neurophysiological experimental studies carried out in neurological and psychiatric patients: (1) recording of rsEEGs (environmental conditions and instructions to participants; montage of the EEG electrodes; recording settings); (2) digital storage of rsEEG and control data; (3) computerized visualization of rsEEGs and control data (identification of artifacts and neuropathological rsEEG waveforms); (4) extraction of "synchronization" features based on frequency analysis (band-pass filtering and computation of rsEEG amplitude/power density spectrum); (5) extraction of "connectivity" features based on frequency analysis (linear and nonlinear measures); (6) extraction of "topographic" features (topographic mapping; cortical source mapping; estimation of scalp current density and dura surface potential; cortical connectivity mapping), and (7) statistical analysis and neurophysiological interpretation of those rsEEG features. As core outcomes, the IFCN Workgroup endorsed the use of the most promising "synchronization" and "connectivity" features for clinical research, carefully considering the limitations discussed in this paper. The Workgroup also encourages more experimental (i.e. simulation studies) and clinical research within international initiatives (i.e., shared software platforms and databases) facing the open controversies about electrode montages and linear vs. nonlinear and electrode vs. source levels of those analyses.

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies.

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer's disease pathology.

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid ß plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aß1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

Can absence seizures be predicted by vigilance states?: Advanced analysis of sleep-wake states and spike-wave discharges' occurrence in rats.

Spike-wave discharges (SWDs) are the main manifestation of absence epilepsy. Their occurrence is dependent on the behavioral state, and they preferentially occur during unstable vigilance periods. The present study investigated whether the occurrence of SWDs can be predicted by the preceding behavioral state and whether this relationship is different between the light and the dark phases of the 24-h day. Twenty-four-hour (12:12 light/dark phases) electroencephalographic (EEG) recordings of 12 Wistar Albino Glaxo, originally bred in Rijswijk (WAG/Rij) rats, a well-known genetic model of absence epilepsy, were analyzed and transformed into sequences of 2-s length intervals of the following 6 possible states: active wakefulness (AW), passive wakefulness (PW), deep slow-wave sleep (DSWS), light slow-wave sleep (LSWS), rapid eye movement (REM) sleep, and SWDs, given discrete series of categorical data. Probabilities of all transitions between states and Shannon entropy of transitions were calculated for the light and dark phases separately and statistically analyzed. Common differences between the light and the dark phases were found regarding the time spent in AW, LSWS, DSWS, and SWDs. The most probable transitions were that AW was preceded and followed by PW and vice versa regardless of the phase of the photoperiod. A similar relationship was found for light and deep slow-wave sleep. The most probable transitions to and from SWDs were AW and LSWS, respectively, with these transition likelihoods being consistent across both circadian phases. The second most probable transitions around SWDs appeared more variable between light and dark. During the light phase, SWDs occurred around PW and participated exclusively in sleep initiation; in the dark phase, SWDs were seen on both, ascending and descending steps towards and from sleep. Conditional Shannon entropy showed that AW and DSWS are the most predictable events, while the possible prediction horizon of SWDs is not larger than 4 s and despite the higher occurrence of SWDs in the dark phase, did not differ between phases. It can be concluded that although SWDs show a stable, strong circadian rhythm with a peak in number during the dark phase, their occurrence cannot be reliably predicted by the preceding behavioral state, except at a very short time base.

Spike-Wave Discharges and Sleep-Wake States during Circadian Desynchronization: No Effects of Agomelatine upon Re-Entrainment.

Rapid changes in the light-dark cycle cause circadian desynchronization between rhythms of spike-wave discharges (SWDs) and motor activity in genetic epileptic rats, and this is accompanied by an increase in epileptic activity. Given the close relationship between absence seizures and sleep-wake states, the present study assessed firstly a putative relationship between vigilance rhythms and SWDs during re-synchronization, and secondly sleep-wake patterns responsible for increased epileptic activity. Lastly, in a view of existing evidence that melatonin and its agonists accelerate re-synchronization, the effects of different doses of agomelatine upon the speed of re-synchronization of different sleep-wake states and SWDs were investigated. Simultaneous electroencephalographic and electromyographic recordings were made in symptomatic WAG/Rij rats, before, during and 10 days following an 8 h light phase delay. Agomelatine was orally administered acutely and sub-chronically, during 10 post-shift days. The magnitude of the advance after the shift and the speed of re-synchronization were specific for various rhythms. Most prominent change was the increase in REM sleep duration during the dark phase. A post-shift increase in passive wakefulness and a reduction in deep slow-wave sleep coincided with an aggravation of SWDs during the light phase. Agomelatine showed neither an effect on sleep-wake parameters and SWDs, nor affected re-synchronization. The same speed of re-synchronization of SWDs and light slow-wave sleep suggests that both are controlled by a common circadian mechanism. The redistribution of SWDs and their increase in the light phase after the shift may be of importance for patients with absence epilepsy planning long trans-meridian flight across time zones.

Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu2 PAMs with high values for kon but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.

Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats.

Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not.

Age-dependent concomitant changes in synaptic dysfunction and GABAergic pathway in the APP/PS1 mouse model.

Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.

mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats.

G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1-10 mg/kg) and JNJ-42153605 (3-30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive.

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications.

The contemporary value of animal pharmaco-electroencephalography (p-EEG)-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. While p-EEG in humans and animals has been shown to be closely related in terms of underlying neuronal substrates, both translational and back-translational approaches are being used to address extrapolation issues and optimize the translational validity of preclinical animal p-EEG paradigms and data. Present applications build further on animal p-EEG and pharmaco-sleep EEG findings, but also on stimulation protocols, more specifically pharmaco-event-related potentials. Pharmaceutical research into novel treatments for neurological and psychiatric diseases has employed an increasing number of pharmacological as well as transgenic models to assess the potential therapeutic involvement of different neurochemical systems and novel drug targets as well as underlying neuronal connectivity and synaptic function. Consequently, p-EEG studies, now also readily applied in modeled animals, continue to have an important role in drug discovery and development, with progressively more emphasis on its potential as a central readout for target engagement and as a (translational) functional marker of neuronal circuit processes underlying normal and pathological brain functioning. In a similar vein as was done for human p-EEG studies, the contribution of animal p-EEG studies can further benefit by adherence to guidelines for methodological standardization, which are presently under construction by the International Pharmaco-EEG Society (IPEG).