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OBJECTIVE: Schizophrenia patients have problems directing attention. Sustained attention requires ensuring that brain resources are focused on a selected target (top-down task) while ignoring irrelevant distractors (bottom-up interference). Whether patients have too little ability to focus or too much interference from distraction has not been clarified. The oddball paradigm embeds infrequent targets and distractors into the stimulus train, and schizophrenia deficits have been linked to diminished responses to both. Cerebral activity underlying abnormal attention can be examined with event-related functional magnetic resonance imaging. METHOD: A visual oddball task was presented to 22 patients with schizophrenia and 28 comparison subjects. Statistical probability maps reflecting blood-oxygenation-level-dependent changes were generated for infrequent targets and novel distractors relative to frequent standard stimuli. Activation was related to performance and symptoms. RESULTS: Activation specific to targets and distractors was associated with faster performance. For targets, patients had diminished activation in superior temporal and frontal gyri, cingulate, thalamus, and basal ganglia. They had increased activation in right insula, mid-frontal gyrus, posterior cingulate, and left inferior parietal lobule. For distractors, patients showed less activation in occipital regions and left inferior parietal lobule but increased activation in parietal-occipital, right mid-frontal, and left inferior frontal gyri. Abnormal activation correlated with positive and negative symptoms. CONCLUSIONS: Abnormal activation in schizophrenia in response to attentional demands reflects both insufficient recruitment of brain systems required for target detection and overcommitment of resources for processing irrelevant distractors. Schizophrenia patients appear to have an inability both to focus on targets and ignore distraction. [ABSTRACT FROM AUTHOR]

Introduction: Deep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks., Methods: In this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice., Results: Imaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters [i.e., gamma (100 Hz)]., Discussion: These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Crown, Agyeman, Choi, Zepeda, Iseri, Pahlavan, Siegel, Liu, Christopoulos and Lee.)

Event-related potentials (ERPs) are small voltage changes in the brain that reliably occur in response to auditory or visual stimuli. ERPs have been extensively studied in both humans and animals to identify biomarkers, test pharmacological agents, and generate testable hypotheses about the physiological and genetic basis of schizophrenia. In this chapter, we discuss how ERPs are generated and recorded as well as review canonical ERP components in the context of schizophrenia research in humans. We then discuss what is known about rodent homologs of these components and how they are altered in common pharmacologic and genetic manipulations used in preclinical schizophrenia research. This chapter will also explore the relationship of ERPs to leading hypotheses about the pathophysiology of schizophrenia. We conclude with an evaluation of both the utility and limitations of ERPs in schizophrenia research and offer recommendations of future directions that may be beneficial to the field., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Competing Interests: HC, SH, and SPR are the Co-Chairs of the Lancet Commission on Medicine, Nazism, and the Holocaust, VR was a Co-Chair of this Lancet Commission until September, 2021, and the other authors are members of this Lancet Commission. TC has received honoraria and travel support for lectures, presentations, and educational events about medicine, Nazism, and the Holocaust from academic institutions only. HC has received travel funding for a Lancet Commission meeting in Jerusalem (2022) and a grant from the Max Planck Society for a project on the history of brain research using Nazi victims' brains. MAF has received funding from the Israel Medical Association for leading seminar tours on medicine and the Holocaust. SH has received royalties from Berghahn Books for The Anatomy of Murder, honoraria from educational institutions for lectures about medicine and anatomy in Nazi Germany, and is an unpaid member of the Harvard Human Remains Research Review Committee and the American Association for Anatomy Task Force on Legacy Collections. EL has received royalties from Classiques Garnier for his book L'Homme, cet inconnu d'Alexis Carrel (1935), serves as an unpaid member of the Israel National Commission according to the Patient at end-of-life Law (2005), and received travel reimbursement for attending a symposium at Cedars Sinai Center for Medicine, Holocaust and Genocide Studies (Los Angeles, CA, USA) and the Lancet Commission meeting in Vienna (2023). MO has received occasional honoraria from educational institutions for lectures on medicine, Nazism, and the Holocaust at educational institutions, as well as travel reimbursement for the Lancet Commission meetings in Jerusalem (2022) and Vienna (2023). AO declares travel reimbursement for attending the Lancet Commission meeting in Vienna (2023). VR received a grant for a project financed by the Max Planck Society on the use of body parts of Nazi victims in brain research. MR received a contract from the district of Upper Bavaria for research and a book project on victims of National Socialist euthanasia starting in October, 2023; received travel reimbursement for presentations on psychiatry in Nazi Germany at educational institutions; and serves as an unpaid member on the advisory boards for Brandenburg memorial sites, Hadamar memorial site, Irsee memorial site, Klingenmünster Psychiatric Hospital, the Bernhard Nocht Institute, the German Society of Pediatrics and Adolescent Medicine, the German Association for Psychiatry, Psychotherapy and Psychosomatics, and the Hessian Ministry of Science. CS received an honorarium from the Max Planck Society (work contract) for participation at the Lancet Commission meeting in Vienna (2023). SJS received travel reimbursement from the Cedars-Sinai Center for Medicine, Holocaust and Genocide Studies for attending the Lancet Commission meeting in Vienna (2023) and has received honoraria from educational institutions for presentations on medicine, Nazism, and the Holocaust. AT has received royalties from Cambridge University Press for the book Social Mendelism: Genetics and the Politics of Race in Germany, 1900–1948, and an honorarium from the University of Leeds (Leeds, UK) for a lecture titled “Mendeling Jews: a history of racial genetics”. HSW has received honoraria from educational institutions for presentations on the legacy of medicine during the Holocaust and professional identity formation. MKW has received a grant from the Macy Foundation for the implementation of this Lancet Commission's first teacher training fellowship; has received honoraria from educational institutions for lectures on medicine and the Holocaust, which he donates to his institution's fund to support programmes related to this history; serves as Co-Chair of the American Medical Association's Truth, Reconciliation, Health and Transformation Task Force (for which he receives an annual honorarium that he donates to his university); and is an unpaid member of the Fellows Council for the Hastings Center and the Advisory Council for Physicians for Human Rights. All other authors declare no competing interests.

Competing Interests: Declaration of interests TC has received honoraria and travel support for lectures, presentations, and educational events about medicine, Nazism, and the Holocaust from academic institutions only. HC has received travel funding for a Lancet Commission meeting in Jerusalem (2022), and a grant from the Max Planck Society for a project on the history of brain research using Nazi victims' brains. MF has received funding from the Israel Medical Association for leading seminar tours on medicine and the Holocaust. SH has received royalties from Berghahn Books for The Anatomy of Murder, honoraria from educational institutions for lectures about medicine and anatomy in Nazi Germany, and is an unpaid member of the Harvard Human Remains Research Review Committee and the American Association for Anatomy Task Force on Legacy Collections. EL has received royalties from Classiques Garnier for his book L'Homme, cet inconnu d'Alexis Carrel, 1935, serves as an unpaid member of the Israel National Commission according to the Patient at end-of-life Law (2005), and received travel reimbursement for attending a symposium at Cedars Sinai Center for Medicine, Holocaust and Genocide Studies (Los Angeles, CA, USA) and the Lancet Commission meeting in Vienna (2023). MO has received occasional honoraria from educational institutions for lectures on medicine, Nazism, and the Holocaust at educational institutions, as well as travel reimbursement for the Lancet Commission meetings in Jerusalem (2022) and Vienna (2023). AO declares travel reimbursement for attending the Lancet Commission meeting in Vienna (2023). VR received a grant for a project financed by the Max Planck Society on the use of body parts of Nazi victims in brain research. MR received a contract from the district of Upper Bavaria for research and a book project on victims of National Socialist euthanasia starting in October, 2023; received travel reimbursement for presentations on psychiatry in Nazi Germany at educational institutions; and serves as an unpaid member on the advisory boards for Brandenburg memorial sites, Hadamar memorial site, Irsee memorial site, Klingenmünster Psychiatric hospital, the Bernhard Nocht Institute, the German Society of Pediatrics and Adolescent Medicine, the German Association for Psychiatry, Psychotherapy and Psychosomatics, and the Hessian Ministry of Science. CS received an honorarium from the Max Planck Society (work contract) for participation at the Lancet Commission meeting in Vienna (2023). SJS received travel reimbursement from the Cedars-Sinai Center for Medicine, Holocaust and Genocide Studies for attending the Lancet Commission meeting in Vienna (2023) and has received honoraria from educational institutions for presentations on medicine, Nazism, and the Holocaust. AT has received royalties from Cambridge University Press for the book Social Mendelism: Genetics and the Politics of Race in Germany, 1900–1948, and an honorarium from the University of Leeds (Leeds, UK) for a lecture titled “Mendeling Jews: a history of racial genetics”. HSW has received honoraria from educational institutions for presentations on the legacy of medicine during the Holocaust and professional identity formation. MKW has received a grant from the Macy Foundation for the implementation of this Commission's first teacher training fellowship; has received honoraria from educational institutions for lectures on medicine and the Holocaust, which he donates to his institution's fund to support programmes related to this history; serves as Co-Chair of the American Medical Association's Truth, Reconciliation, Health and Transformation Task Force (for which he receives an annual honorarium that he donates to his university); and is an unpaid member of the Fellows Council for the Hastings Center and the Advisory Council for Physicians for Human Rights. All other authors declare no competing interests.

Background: Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with broad medical and psychiatric morbidity, and obesity. While BED may be characterized by altered cortical morphometry, no evidence to date examined possible sex-differences in regional gray matter characteristics among those with BED. This is especially important to consider in children, where BED symptoms often emerge coincident with rapid gray matter maturation., Methods: Pre-adolescent, 9-10-year old boys ( N = 38) and girls ( N = 33) with BED were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development Study. We investigated sex differences in gray matter density (GMD) via voxel-based morphometry. Control sex differences were also assessed in age and body mass index and developmentally matched control children (boys N = 36; girls N = 38). Among children with BED, we additionally assessed the association between dorsolateral prefrontal (dlPFC) GMD and parent-reported behavioral approach and inhibition tendencies., Results: Girls with BED uniquely demonstrate diffuse clusters of greater GMD ( p < 0.05, Threshold Free Cluster Enhancement corrected) in the (i) left dlPFC ( p = 0.003), (ii) bilateral dmPFC ( p = 0.004), (iii) bilateral primary motor and somatosensory cortex ( p = 0.0003) and (iv) bilateral precuneus ( p = 0.007). Brain-behavioral associations suggest a unique negative correlation between GMD in the left dlPFC and behavioral approach tendencies among girls with BED., Conclusions: Early-onset BED may be characterized by regional sex differences in terms of its underlying gray matter morphometry.

Background: Behavioral features of binge eating disorder (BED) suggest abnormalities in reward and inhibitory control. Studies of adult populations suggest functional abnormalities in reward and inhibitory control networks. Despite behavioral markers often developing in children, the neurobiology of pediatric BED remains unstudied., Methods: 58 pre-adolescent children (aged 9-10-years) with BED ( m BMI = 25.05; s.d. = 5.40) and 66 age, BMI and developmentally matched control children ( m BMI = 25.78; s.d. = 0.33) were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in resting-state functional MRI functional connectivity (FC) within and between reward and inhibitory control networks. A seed-based approach was employed to assess nodes in the reward [orbitofrontal cortex (OFC), nucleus accumbens, amygdala] and inhibitory control [dorsolateral prefrontal cortex, anterior cingulate cortex (ACC)] networks via hypothesis-driven seed-to-seed analyses, and secondary seed-to-voxel analyses., Results: Findings revealed reduced FC between the dlPFC and amygdala, and between the ACC and OFC in pre-adolescent children with BED, relative to controls. These findings indicating aberrant connectivity between nodes of inhibitory control and reward networks were corroborated by the whole-brain FC analyses., Conclusions: Early-onset BED may be characterized by diffuse abnormalities in the functional synergy between reward and cognitive control networks, without perturbations within reward and inhibitory control networks, respectively. The decreased capacity to regulate a reward-driven pursuit of hedonic foods, which is characteristic of BED, may in part, rest on this dysconnectivity between reward and inhibitory control networks.

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2 + channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Few treatments exist for the cognitive symptoms of schizophrenia. Pharmacological agents resulting in glutamate N-methyl-d-aspartate (NMDA) receptor hypofunction, such as MK-801, mimic many of these symptoms and disrupt neural activity. Recent evidence suggests that deep brain stimulation (DBS) of the medial septal nucleus (MSN) can modulate medial prefrontal cortex (mPFC) and hippocampal activity and improve spatial memory., Objective: Here, we examine the effects of acute MK-801 administration on oscillatory activity within the septohippocampal circuit and behavior. We also evaluate the potential for MSN stimulation to improve cognitive behavioral measures following MK-801 administration., Methods: 59 Sprague Dawley male rats received either acute intraperitoneal (IP) saline vehicle injections or MK-801 (0.1 mg/kg). Theta (5-12 Hz), low gamma (30-50 Hz) and high frequency oscillatory (HFO) power were analyzed in the mPFC, MSN, thalamus and hippocampus. Rats underwent MSN theta (7.7 Hz), gamma (100 Hz) or no stimulation during behavioral tasks (Novel object recognition (NOR), elevated plus maze, Barnes maze (BM))., Results: Injection of MK-801 resulted in frequency-specific changes in oscillatory activity, decreasing theta while increasing HFO power. Theta, but not gamma, stimulation enhanced the anxiolytic effects of MK-801 on the elevated plus maze. While MK-801 treated rats exhibited spatial memory deficits on the Barnes maze, those that also received MSN theta, but not gamma, stimulation found the escape hole sooner., Conclusions: These findings demonstrate that acute MK-801 administration leads to altered neural activity in the septohippocampal circuit and impaired spatial memory. Further, these findings suggest that MSN theta-frequency stimulation improves specific spatial memory deficits and may be a possible treatment for cognitive impairments caused by NMDA hypofunction., (Published by Elsevier Inc.)

Background: Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents., Methods: The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4)., Results: Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort., Conclusions: Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with an array of multisystemic organ morbidity, broad psychiatric morbidity, and obesity. Despite behavioral markers often developing in early childhood, the neurobiological markers of early-onset BED remain understudied, and developmental pathophysiology remains poorly understood., Methods: 71 preadolescent children (aged 9-10-years) with BED and 74 age, BMI and developmentally matched control children were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in gray matter density (GMD) via voxel-based morphometry (VBM). We additionally performed region of interest analyses, assessing the association between GMD in nodes of the reward (orbitofrontal cortex; OFC) and inhibitory control (dorsolateral prefrontal cortex; dlPFC) networks, and parent-reported behavioral inhibition and approach tendencies., Results: Diffuse elevations in cortical GMD were noted in those with BED, which spanned prefrontal, parietal, and temporal regions. No areas of reduced GMD were noted in those with BED. No alterations in subcortical GMD were noted. Brain-behavioral associations suggest a distinct and negative relationship between GMD in the OFC and dlPFC, respectively, and self-reported markers of hedonic behavioral approach tendencies., Conclusions: Early-onset BED may be characterized by diffuse morphological abnormalities in gray matter density, suggesting alterations in cortical architecture which may reflect decreased synaptic pruning and arborization, or decreased myelinated fibers and therefore inter-regional afferents., (Copyright © 2022 Elsevier B.V. All rights reserved.)

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development.

Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.

Social affiliative behavior is an important component of everyday life in many species and is likely to be disrupted in disabling ways in various neurodevelopmental and neuropsychiatric disorders. Therefore, determining the mechanisms involved in these processes is crucial. A link between N-methyl-d-aspartate (NMDA) receptor function and social behaviors has been clearly established. The cell types in which NMDA receptors are critical for social affiliative behavior, however, remain unclear. Here, we use mice carrying a conditional allele of the NMDA R1 subunit to address this question. Mice bearing a floxed NMDAR1 (NR1) allele were crossed with transgenic calcium/calmodulin-dependent kinase IIα (CaMKIIα)-Cre mice or parvalbumin (PV)-Cre mice targeting postnatal excitatory forebrain or PV-expressing interneurons, respectively, and assessed using the three-chambered Social Approach Test. We found that deletion of NR1 in PV-positive interneurons had no effect on social sniffing, but deletion of NR1 in glutamatergic pyramidal cells resulted in a significant increase in social approach behavior, regardless of age or sex. Therefore, forebrain excitatory neurons expressing NR1 play an important role in regulating social affiliative behavior., (© 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Metatarsus adductus is a common transverse plane congenital foot deformity. Achieving anatomic correction can be challenging, as all osteotomy procedures have a steep learning curve. A multitude of complications can occur when using traditional pan-metatarsal osteotomy approaches. The modified Lepird procedure is performed with proximal base osteotomies on all 5 metatarsals oriented dorsal distal to plantar proximal. All screws are inserted parallel to each other, allowing the forefoot to move laterally as a unit. The foot and ankle surgeon is able to dial in with precision the exact amount of forefoot abduction necessary to correct the deformity. The modified Lepird procedure dynamically corrects the metatarsus adductus deformity so it can easily prevent any over- or undercorrection that may occur intraoperatively. The author recommends this procedure when pan-metatarsal base osteotomies are required for correction of metatarsus adductus and associated deformities., (Copyright © 2018 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Much evidence suggests that hypofunction of the N-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways. We recently showed reduced Src signaling in post mortem tissue from schizophrenia patients, despite increased MK-801 binding and NMDA receptor complex expression in the postsynaptic density (PSD). These data suggest that Src dysregulation may be an important underlying mechanism responsible for reduced glutamate signaling. Despite this evidence for a central role of Src in NMDAR signaling, little is known about how reductions in Src activity might regulate phenotypic changes in cognition and behavior. As such, the current study sought to characterize behavioral and electrophysiological phenotypes in mice heterozygous for the Src Acl gene (Src+/- mice). Src+/- mice demonstrated decreased sociability and working memory relative to Src+/+ (WT) mice while no significant differences were seen on locomotive activity and anxiety-related behavior. In relation to WT mice, Src+/- mice showed decreased mid-latency P20 auditory event related potential (aERP) amplitudes, decreased mismatch negativity (MMN) and decreased evoked gamma power, which was only present in males. These data indicate that Src+/- mice are a promising new model to help understand the pathophysiology of these electrophysiological, behavioral and cognitive changes. As such, we propose that Src+/- mice can be used in the future to evaluate potential therapeutic approaches by targeting increased Src activity as a common final pathway for multiple etiologies of SCZ and other diseases characterized by reduced glutamate function., (Copyright © 2019. Published by Elsevier Inc.)

Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.

Altered gamma-band electrophysiological activity in individuals with autism spectrum disorder (ASD) is well documented, and analogous gamma-band alterations are recapitulated in several preclinical murine models relevant to ASD. Such gamma-band activity is hypothesized to underlie local circuit processes. Gamma-band cross-frequency coupling (CFC), a related though distinct metric, interrogates local neural circuit signal integration. Several recent studies have observed perturbed gamma-band CFC in individuals with ASD, although the direction of change remains unresolved. It also remains unclear whether murine models relevant to ASD recapitulate this altered gamma-band CFC. As such, this study examined whether mice with parvalbumin (PV) cell-specific ablation of NMDA-R1 (PV cre /NR1 fl/fl ) demonstrated altered gamma-band CFC as compared with their control littermates (PV cre /NR1 +/+ -mice that do not have the PV cell-specific ablation of NMDA-R1). Ten mice of each genotype had 4 min of "resting" electroencephalography recorded and analyzed. First, resting electrophysiological power was parsed into the canonical frequency bands and genotype-related differences were subsequently explored so as to provide context for the subsequent CFC analyses. PV cre /NR1 fl/fl mice exhibited an increase in resting power specific to the high gamma-band, but not other frequency bands, as compared with PV cre /NR1 +/+ . CFC analyses then examined both the standard magnitude (strength) of CFC and the novel metric Phase Max -which denotes the phase of the lower frequency signal at which the peak higher frequency signal power occurred. PV cre /NR1 fl/fl mice exhibited altered Phase Max , but not strength, of gamma-band CFC as compared with PV cre /NR1 +/+ mice. As such, this study suggests a potential novel metric to explore when studying neuropsychiatric disorders.

Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.

Schizophrenia is a mental disorder associated with profoundly disruptive positive and negative symptomology that result in difficulties building close relationships with others, performing daily tasks and sustaining independent living, resulting in poor social, vocational and occupational attainment (functional outcome). Mismatch Negativity (MMN) is a change in the sensory event-related potential that occurs in response to deviation from an established pattern of stimulation. Patients with schizophrenia show a reduction in MMN that is positively associated with impaired cognition and poor functional outcome. This has led to interest in MMN as a potential clinical and pre-clinical biomarker of fundamental neural processes responsible for reduced functional outcome. To date, relatively few studies have sought to assess MMN in non-human primates or rodents. The validity of these studies will be reviewed using criteria used to identify true deviance detection based MMN responses in human subjects. Although MMN has been difficult to establish in pre-clinical models the weight of evidence suggests that non-human animals show true deviance based MMN., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10 +/- ) has been investigated as a proxy for ASD. Male Pcdh10 +/- mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10 +/- mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10 +/- mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10 +/- mice, male Pcdh10 +/- mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10 +/- mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABA B agonist remediated these electrophysiological alterations among male Pcdh10 +/- mice. Pcdh10 +/- mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10 +/- mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Studies suggest that the amygdala is a key region for regulation of anxiety, fear and social function. Therefore, dysfunction of the amygdala has been proposed as a potential mechanism for negative symptoms in schizophrenia. This may be due to NMDA receptor-mediated hypofunction, which is thought to be related to the pathogenesis of schizophrenia. In this study, electroencephalographic amygdala activity was assessed in mice during the three-chamber social test. This activity was also evaluated following exposure to the NMDA receptor antagonist ketamine. Vehicle-treated mice spent significantly more time in the social than the non-social chamber. This social preference was eliminated by ketamine. However, ketamine-treated mice spent significantly less time in the social chamber and significantly more time in the nonsocial chamber than vehicle-treated mice. There were no significant differences in induced powers between social and non-social chamber entries in vehicle-treated mice, except for theta frequencies, which featured greater induced theta power during non-social chamber entry. Ketamine eliminated differences in induced theta power between social and non-social chamber entries. Moreover, ketamine increased the induced gamma power during social chamber entry compared to that of vehicle-treated mice. All other frequency ranges were not significantly influenced by zone or drug condition. All significant findings were upon entry to chambers not during interaction. Results suggest that impaired function of NMDA receptor-mediated glutamate transmission can induce social impairments and amygdala dysfunction, similar to the pattern in schizophrenia. Future studies will utilize this method to evaluate mechanisms of social dysfunction and development of treatments of social impairments in schizophrenia., (Copyright © 2017. Published by Elsevier B.V.)

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30-80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Schizophrenia (SCZ) is a disorder characterized by positive symptoms (hallucinations, delusions), negative symptoms (blunted affect, alogia, reduced sociability, and anhedonia), as well as persistent cognitive deficits (memory, concentration, and learning). While the biology underlying subjective experiences is difficult to study, abnormalities in electroencephalographic (EEG) measures offer a means to dissect potential circuit and cellular changes in brain function. EEG is indispensable for studying cerebral information processing due to the introduction of techniques for the decomposition of event-related activity into its frequency components. Specifically, brain activity in the gamma frequency range (30-80Hz) is thought to underlie cognitive function and may be used as an endophenotype to aid in diagnosis and treatment of SCZ. In this review we address evidence indicating that there is increased resting-state gamma power in SCZ. We address how modeling this aspect of the illness in animals may help treatment development as well as providing insights into the etiology of SCZ., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Activation of NMDA receptors can induce iron movement into neurons by the small GTPase Dexras1 via the divalent metal transporter 1 (DMT1). This pathway under pathological conditions such as NMDA excitotoxicity contributes to metal-catalyzed reactive oxygen species (ROS) generation and neuronal cell death, and yet its physiological role is not well understood., Results: We found that genetic and pharmacological ablation of this neuronal iron pathway in the mice increased glutamatergic transmission. Voltage sensitive dye imaging of hippocampal slices and whole-cell patch clamping of synaptic currents, indicated that the increase in excitability was due to synaptic modification of NMDA receptor activity via modulation of the PKC/Src/NR2A pathway. Moreover, we identified that lysosomal iron serves as a main source for intracellular iron signaling modulating glutamatergic excitability., Conclusions: Our data indicates that intracellular iron is dynamically regulated in the neurons and robustly modulate synaptic excitability under physiological condition. Since NMDA receptors play a central role in synaptic neurophysiology, plasticity, neuronal homeostasis, neurodevelopment as well as in the neurobiology of many diseases, endogenous iron is therefore likely to have functional relevance to each of these areas.

The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia., Significance Statement: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV., (Copyright © 2015 the authors 0270-6474/15/3516282-13$15.00/0.)

Background: Ketamine, an N-methyl-d-aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure., Methods: We examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2., Results: Juvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone., Conclusions: Data suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Frequent ketamine abuse in adulthood correlates with increased risk of psychosis, as well as cognitive deficits, including disruption of higher-order executive function and memory formation. Although the primary abusers of ketamine are adolescents and young adults, few studies have evaluated its effects on juvenile cognition. Therefore, the current study analyzes the effect of adolescent ketamine exposure on cognitive development. Juvenile mice (4 weeks of age) were exposed to chronic ketamine (20 mg kg(-1), i.p. daily) for 14 days. Mice were tested immediately after exposure in the juvenile period (7 weeks of age) and again as adults (12 weeks of age). Measures included electroencephalography (EEG) in response to auditory stimulation, the social choice test, and a 6-arm radial water maze task. Outcome measures include low-frequency EEG responses, event-related potential (ERP) amplitudes, indices of social behavior and indices of spatial working memory. Juvenile exposure to ketamine was associated with electrophysiological abnormalities in adulthood, particularly in induced theta power and the P80 ERP. The social choice test revealed that ketamine-exposed mice failed to exhibit the same age-related decrease in social interaction time as controls. Ketamine-exposed mice outperformed control mice as juveniles on the radial water maze task, but did not show the same age-related improvement as adult controls. These data support the hypothesis that juvenile exposure to ketamine produces long-lasting changes in brain function that are characterized by a failure to progress along normal developmental trajectories.

Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-α (RPTPα) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations., Competing Interests: The authors have no conflict of interest in relation to the work described.

Standard dopamine therapies for schizophrenia are not efficacious for negative symptoms of the disease, including asociality. This reduced social behavior may be due to glutamatergic dysfunction within the amygdala, leading to increased fear and social anxiety. Several studies have demonstrated the prosocial effects of oxytocin in schizophrenia patients. Therefore, this study evaluates the effect of subchronic oxytocin on EEG activity in amygdala of mice during performance of the three-chamber social choice and open field tests following acute ketamine as a model of glutamatergic dysfunction. Oxytocin did not restore social deficits introduced by ketamine but did significantly increase sociality in comparison to the control group. Ketamine had no effect on time spent in the center during the open field trials, whereas oxytocin increased overall center time across all groups, suggesting a reduction in anxiety. Amygdala activity was consistent across all drug groups during social and nonsocial behavioral trials. However, oxytocin reduced overall amygdala EEG power during the two behavioral tasks. Alternatively, ketamine did not significantly affect EEG power throughout the tasks. Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors. Data suggest that separate prosocial and social anxiety pathways may mediate social preference., ((c) 2015 APA, all rights reserved).)

Infections are a common cause of infant mortality worldwide, especially due to Streptococcus pneumoniae. Colonization is the prerequisite to invasive pneumococcal disease, and is particularly frequent and prolonged in children, though the mechanisms underlying this susceptibility are unknown. We find that infant mice exhibit prolonged pneumococcal carriage, and are delayed in recruiting macrophages, the effector cells of clearance, into the nasopharyngeal lumen. This lack of macrophage recruitment is paralleled by a failure to upregulate chemokine (C-C) motif ligand 2 (Ccl2 or Mcp-1), a macrophage chemoattractant that is required in adult mice to promote clearance. Baseline expression of Ccl2 and the related chemokine Ccl7 is higher in the infant compared to the adult upper respiratory tract, and this effect requires the infant microbiota. These results demonstrate that signals governing macrophage recruitment are altered at baseline in infant mice, which prevents the development of appropriate innate cell infiltration in response to pneumococcal colonization, delaying clearance of pneumococcal carriage.

Studies suggest that abnormalities in glutamate and GABA signaling contribute to deficits in schizophrenia and related conditions and that these neurochemical abnormalities produce changes in electroencephalographic (EEG) indices, including event-related potentials and event-related power within specific frequency ranges. Furthermore, clinical studies suggest that a subset of EEG biomarkers is associated with symptoms. This review addresses the relationship between EEG and behavior in preclinical models of N-methyl-d-aspartate (NMDA)-receptor hypofunction, as well as how these models can be used to screen therapies. Data from schizophrenia patients are juxtaposed with data from animal models, and EEG and behavioral data from mice with disruption of NMDA receptors in excitatory and/or inhibitory neurons are then compared to the pattern observed in schizophrenia. Also discussed are results following exposure to potential therapeutic agents, including GABAB agonists. Furthermore, evidence demonstrates that elevated resting gamma power is associated with deficits in social interactions. Consistent with elevated baseline noise, excitatory neurons from transgenic mice show increased intrinsic excitability in in vitro-slice patch-clamp studies across model systems. GABAB receptor agonists reduce this excitability, improve gamma-band responses, and reverse behavioral deficits in mice. Data suggest that baseline gamma power is associated with social function and GABAB agonists may be useful for schizophrenia. Translational EEG biomarkers reflect target engagement and can contribute to the design of more efficient drug trials, likely accelerating the development of new therapeutics for central nervous system disorders., (© 2015 New York Academy of Sciences.)

Background: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear., Methods: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice., Results: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability., Conclusions: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorders (ASD) are characterized by social impairments and restricted/stereotyped behaviors and currently affect an estimated 1 in 68 children aged 8 years old. While there has been substantial recent focus on ASD in research, both the biological pathology and, perhaps consequently, a fully effective treatment have yet to be realized. What has remained throughout is the hypothesis that ASD has neurobiological underpinnings and the observation that both the phenotypic expression and likely the underlying etiology is highly heterogeneous. Given the neurodevelopmental basis of ASD, a biologically based marker (biomarker) could prove useful not only for diagnostic and prognostic purposes, but also for stratification and response indices for pharmaceutical development. In this review, we examine the current state of the field for MEG-related biomarkers in ASD. We describe several potential biomarkers (middle latency delays [M50/M100], mismatch negativity latency, gamma-band oscillatory activity), and investigate their relation to symptomology, core domains of dysfunction (e.g., language impairment), and putative biological underpinnings.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS., (Copyright © 2015 the authors 0270-6474/15/350396-13$15.00/0.)