Since the introduction of second-generation antipsychotics, antipsychotics have been increasingly prescribed for children and adolescents, raising concerns about their long-term impact on neurodevelopment. Antipsychotics block dopaminergic and serotonergic receptors, potentially disrupting the maturation of neurocognitive processes, which is a public health concern. Previous studies have reported that adolescent antipsychotic treatment can cause persistent neurocognitive dysfunction in rodents, yet the neurobiological underpinnings remain unknown. To address this, we administered risperidone, a commonly used antipsychotic, to C57BL/6 mice during adolescence (3 to 6 weeks of age) and examined behavioral and neurobiological outcomes nine weeks post-treatment. Risperidone-treated mice exhibited subtle deficits in behavioral correlates of anxiety-like behavior. In vivo, two-photon calcium imaging of cortical neurons revealed a remarkable increase in the amplitude of calcium events with subtle sex-specific changes in the frequency, consistent with increased neuronal excitability. Single-nucleus RNA-sequencing (snRNA-seq) analyses showed widespread reductions in transcripts for voltage-sensitive and inwardly rectifying potassium channels in both pyramidal neurons and interneurons. Additionally, both cell types exhibited reduced Grin2a and Grin2b, as well as scaffolding proteins, indicative of weakened synaptic connectivity between excitatory and inhibitory neurons. Interestingly, we observed sex-dependent differences in the directionality of correlation between certain gene co-expression modules and risperidone treatment. Our results suggest that adolescent risperidone treatment induces lasting transcriptomic and functional changes associated with altered excitatory-inhibitory neuronal interactions that may underline cognitive and behavioral dysregulations.

The complex and heterogeneous genetic architecture of neuropsychiatric illnesses compels us to look beyond individual risk genes for therapeutic strategies and target the interactive dynamics and convergence of their protein products. A mechanistic substrate for convergence of synaptic neuropsychiatric risk genes are protein-protein interactions (PPIs) in the N-methyl-D-aspartate receptor (NMDAR) complex. NMDAR hypofunction in schizophrenia is associated with hypoactivity of Src kinase, resulting from convergent alterations in PPIs of Src with its partners. Of these, the association of Src with PSD-95, which inhibits the activity of this kinase in the NMDAR complex, is known to be increased in schizophrenia. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 by employing a cell-penetrating and Src-activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP enhanced synaptic NMDAR currents in Src+/- and Sdy-/- mice manifesting NMDAR hypofunction phenotypes. Chronic intracerebroventricularly (ICV) injection of TAT-SAPIP rescued cognitive deficits in trace fear conditioning in Src +/- mice. Moreover, TAT-SAPIP enhanced Src activity in synaptoneurosomes derived from dorsolateral prefrontal cortex of 14 patients. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

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.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

Adolescent social stress can be detrimental to developing hippocampal-prefrontal circuits and is associated with psychiatric outcomes. We previously found that adolescent social instability stress (SIS) in mice resulted in later-life novel object recognition (NOR) impairment. NOR performance was correlated with RNA expression of complement proteins C1q and CR3 in control but not SIS mice. We hypothesized that SIS alters the innate immune system, impacting inter-regional neuronal communication and memory function.

Pediatric gastroenterology patients are at risk for co-occurring behavioral health concerns, such as depression and anxiety, compared with youth without medical conditions. The objective of this systematic review was to assess the scientific literature supporting the hypothesis that integrating behavioral health services into gastroenterology clinics could improve patient psychosocial well-being. We searched MEDLINE, EMBASE, The Cochrane Library, Web of Science, PsycINFO, and CINAHL databases and gray literature to identify studies reporting the impact of behavioral health integration on the psychosocial well-being of pediatric gastroenterology patients. Two independent coders evaluated each study for inclusion and extracted data regarding patient demographics, study design, behavioral health integration approaches, and psychosocial outcomes. Results were synthesized using narrative review procedures. Eighteen studies met the inclusion criteria. Most reported outcomes from research grant-funded randomized controlled trials or open trials investigating behavioral health interventions based on Cognitive-Behavioral Therapy, primarily with youth with irritable bowel disease or functional gastrointestinal disorders. Within the highest-quality, comparable studies, nearly 80% reported at least one statistically significant treatment effect on patient psychosocial well-being. Many studies used rigorous methods that minimize bias, but did not provide models for sustainable, programmatic behavioral health integration outside the bounds of a research study. The studies included in this review suggest that behavioral integration could have the potential to positively impact gastroenterology patients' psychosocial functioning. However, more research is needed to investigate the appropriate intensity of behavioral health services and evaluate models for integrating behavioral healthcare in pediatric gastroenterology settings beyond the research-funded clinical trial context.

Back to table of contents Previous article Next article EditorialsFull AccessThe Power of PotentialsSteven Siegel, M.D., Ph.D., Lindsey Crown, Ph.D., Robert Featherstone, Ph.D.Steven SiegelSearch for more papers by this author, M.D., Ph.D., Lindsey CrownSearch for more papers by this author, Ph.D., Robert FeatherstoneSearch for more papers by this author, Ph.D.Published Online:1 Jul 2023https://doi.org/10.1176/appi.ajp.20230400AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The priority data letter by Joshi and colleagues in this issue of the Journal (1) elegantly describes the potential use of auditory event-related potentials (ERPs) for understanding both the biological basis of circuit abnormalities in schizophrenia and the impact of anticholinergic activity on these circuits. Auditory ERPs are created by presenting stimuli (tones or clicks) dozens to hundreds of times and recording electroencephalographic (EEG) responses following each stimulus. This EEG response is recorded via scalp electrodes as a continuous stream of data during the period following each stimulus and contains the summation of all brain activity occurring at that time. Each electrode is like an electrical “microphone,” listening to millions of musical instruments simultaneously—neurons in the entire brain—and combining what it hears into a single output. Unlike music, electrical brain activity can register either as a positive or negative signal at any given moment. Since the brain activity response to the auditory stimulus occurs identically (i.e., neural activity at the same time and in the same way) after each stimulus, that pattern of brain activity will be represented within the EEG response after each stimulus. However, brain activity that is unrelated (and therefore not time-locked) to the stimulus (e.g., visual, olfactory, tactile, or cognitive activity), will generate a series of random positive and negative voltage values, such that their average over many trails will be zero. As such, the averaged activity in the periods following the stimuli will retain auditory-related activity and remove the unrelated activity. The resulting ERP is demonstrated in Figure 1 of the report by Joshi and colleagues. Resulting components of the auditory ERP are typically named using a convention that combines their direction (positive or negative) and either their timing or order after a stimulus. For example, P denotes a positive deflection and N denotes a negative one. The number following the P or N can denote the number of milliseconds (msec) after stimulus onset, e.g., the P50 is a positive deflection at 50 msec after the stimulus while the N100 is a negative deflection at 100 msec after onset. Alternatively, these components can also be named by their order, such that the P1 is the first major positive deflection while the N1 is the first major negative deflection after a stimulus. Joshi and colleagues focus on two components of the auditory ERP response, mismatch negativity (MMN) and P3a, which refer to changes in the pattern of neural response following a change in auditory stimulus characteristics. The MMN occurs as an exaggerated negative deflection directly following the N1 or N100, while the P3 is the third major positive deflection, which is manifest as an exaggeration of the positive deflection following the P2. Both components are elicited when there is a change in qualitative features of a consistent repetitive stimulus (e.g., tone of the stimulus) (2).Many previous studies have employed auditory ERPs to query the integrity and fidelity of neuronal synchrony and connectivity across brain regions. For a comprehensive review of EEG biomarkers, please see the review by Javitt and colleagues (3). The study by Joshi et al. follows previous work by the authors isolating the anticholinergic contribution of various medications as a causative factor in cognitive disability. It then uses deviance-related ERPs as a tool to detect such disturbance and therefore predict potential adverse cognitive consequences of future medications during clinical trials. There are many reasons why the MMN and P3a ERPs are a powerful translational tool, including the ability to control quantitative features of the inputs to a circuit, as well as measuring neuronal processing within and between specific brain regions. Furthermore, this approach allows for preclinical studies that manipulate and isolate the contribution of various genes, neurotransmitters, and pharmacological agents on ERPs (4, 5). However, different studies often ascribe different pharmacological causes for the same outcomes. For example, one study may test the isolated impact of dopamine on ERPs, while another may show similar effects the impact of glutamate on the same ERPs (2). Additionally, antipsychotics, as well as medications that counteract their side effects, have diverse pharmacological properties, making it difficult to ascribe the impact of a drug’s activity at any one neurotransmitter system to their effects on ERPs (6).Prior efforts to predict clinical outcomes of a potential therapeutic agent using preclinical behavior, electrophysiology, and molecular data in rodents have yielded mixed success (7). Additionally, correlational studies linking various ERP components to specific human clinical domains have not consistently translated to the predictive ability to pharmacologically manipulate an ERP component and subsequently move a human clinical outcome (8). This is likely because ascribing any one mechanism for a specific ERP deficit (e.g., glutamatergic contribution to reduced N1 amplitude) is unlikely to account for the full constellation of etiologies and pathophysiologies for that electrophysiological change across different people and disease states (e.g., schizophrenia). That is, if MMN is diminished by a variety of factors, it is impossible to know which of those factors is contributing to that diminution in a specific clinical population, let alone a specific person. Similarly, several factors (e.g., genes, medications, developmental events) may be simultaneously at play in humans, such that remediating any one is insufficient to move the relevant circuit in a way that maps on to cognitive or emotional performance. The current study addresses this limitation by examining the association between antimuscarinic cholinergic activity and MMN/P3a amplitude while controlling for other pharmacological factors that might impact these measures. It does so by using a tool that consolidates anticholinergic binding affinity and concentration to a single dimension on a six-point scale. This approach is similar to that used in landmark studies of antipsychotic medications to approximate receptor occupancy in vivo and definitively demonstrate that these medications work through binding at dopamine type two (D2) receptors (9, 10). It would be helpful to address the specificity of the relationship between cognitive impairment and anticholinergic activity by performing similar analyses for the myriad pharmacologic activities of antipsychotic and other agents, including binding at serotonergic, histaminic, noradrenergic, and other neurotransmitter systems. Future studies could replicate the approach by Joshi et al. to evaluate the extent to which other neurotransmitter systems modulate the effects of pharmacological agents on MMN, P3a, and cognitive performance in humans. Such an analysis would be enabled by using data for affinity of multiple agents at these other receptors, potentially in the subjects who participated in the current study. A limitation would likely be the paucity of glutamatergic agents that are used in populations for which cognitive tests and ERPs are available. Indeed, much prior work has focused on glutamatergic contributions to MMN and P3a using pharmacologic and genetic approaches (4, 11, 12). Similarly, several studies have also examined the contributions of nicotine (13–15).Another limitation of ERPs or other measures of brain electrical activity (e.g., power spectral time frequency decomposition) in complex neural systems, like those impaired in schizophrenia, is the complexity of the measure itself. ERPs are summations of all coordinated neural activity that occurs following a stimulus. While we may be able to demonstrate changes in large, complex brain networks related to ERPs, preclinical studies also demonstrate that there are many circuits related to one electrical rhythm, and many rhythms that can be generated from one circuit (16, 17). One neural network can yield many outcomes, just as many different networks can yield the same overall patterns of electrical activity. Alternatively stated, there are many mechanistic paths that produce the same EEG alterations. It is also important to note that changing the activity of a network can also change the network properties (18). This has been shown for neuromodulatory approaches like transcranial magnetic stimulation (TMS) and is presumably true for activity-dependent changes such as those engaged by cognitive remediation or targeted auditory cognitive testing (TCT). Thus, it is possible that the detrimental impact of anticholinergic medications on brain regions and circuits responsible for MMN/P3a could be counteracted with activity-based augmentation of these same underlying brain regions and circuits. As such, cognitive rehabilitation strategies could be prescribed in patients who have high anticholinergic burden to attenuate unwanted pharmacologic impact on cognition. The current work from Joshi and colleagues is an excellent step in capitalizing on the power of ERPs, while also highlighting how much work is left to be done if we are to truly link such biomarkers to better treatments. The use of ERPs could become a clinical tool to track personalized progression of medication effects in concert with regular cognitive testing in our journey to practice personalized mental health.Department of Psychiatry and the Behavioral Sciences, USC Keck School of Medicine, Los Angeles.Send correspondence to Dr. Siegel ([email protected]).Dr. Siegel has served as a consultant for Almatica, Skyland Trail, and Zynerba, and receives royalties from Teva Pharmaceuticals. The other authors report no financial relationships with commercial interests.References1. Joshi YB, Molina JL, Braff DL, et al.: Sensitivity of schizophrenia endophenotype biomarkers to anticholinergic medication burden. Am J Psychiatry 2023; 180:519–523Link, Google Scholar2. Featherstone RE, McMullen MF, Ward KR, et al.: EEG biomarkers of target engagement, therapeutic effect, and disease process. Ann N Y Acad Sci 2015; 1344:12–26Crossref, Medline, Google Scholar3. Javitt DC, Siegel SJ, Spencer KM, et al.: A roadmap for development of neuro-oscillations as translational biomarkers for treatment development in neuropsychopharmacology. Neuropsychopharmacology 2020; 45:1411–1422Crossref, Medline, Google Scholar4. Ehrlichman RS, Maxwell CR, Majumdar S, et al.: Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice. J Cogn Neurosci 2008; 20:1403–1414Crossref, Medline, Google Scholar5. Siegel SJ, Connolly P, Liang Y, et al.: Effects of strain, novelty, and NMDA blockade on auditory-evoked potentials in mice. Neuropsychopharmacology 2003; 28:675–682Crossref, Medline, Google Scholar6. Arnt J, Skarsfeldt T: Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 1998; 18:63–101Crossref, Medline, Google Scholar7. Markou A, Chiamulera C, Geyer MA, et al.: Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 2009; 34:74–89Crossref, Medline, Google Scholar8. Turetsky BI, Bilker WB, Siegel SJ, et al.: Profile of auditory information-processing deficits in schizophrenia. Psychiatry Res 2009; 165:27–37Crossref, Medline, Google Scholar9. Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192:481–483Crossref, Medline, Google Scholar10. Seeman P, Lee T, Chau-Wong M, et al.: Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261:717–719Crossref, Medline, Google Scholar11. Saunders JA, Gandal MJ, Roberts TP, et al.: NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders. Behav Brain Res 2012; 234:233–237Crossref, Medline, Google Scholar12. Ward KR, Featherstone RE, Naschek MJ, et al.: Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93:84–92Crossref, Medline, Google Scholar13. Smith DM, Fisher D, Blier P, et al.: The separate and combined effects of monoamine oxidase A inhibition and nicotine on the mismatch negativity event related potential. Pharmacol Biochem Behav 2015; 137:44–52Crossref, Medline, Google Scholar14. Knott V, Impey D, Philippe T, et al.: Modulation of auditory deviance detection by acute nicotine is baseline and deviant dependent in healthy nonsmokers: a mismatch negativity study. Hum Psychopharmacol 2014; 29:446–458Crossref, Medline, Google Scholar15. Engeland C, Mahoney C, Mohr E, et al.: Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer’s disease: an event-related potential study. Pharmacol Biochem Behav 2002; 72:457–464Crossref, Medline, Google Scholar16. White RS, Nusbaum MP: The same core rhythm generator underlies different rhythmic motor patterns. J Neurosci 2011; 31:11484–11494Crossref, Medline, Google Scholar17. Prinz AA, Bucher D, Marder E: Similar network activity from disparate circuit parameters. Nat Neurosci 2004; 7:1345–1352Crossref, Medline, Google Scholar18. Temporal S, Desai M, Khorkova O, et al.: Neuromodulation independently determines correlated channel expression and conductance levels in motor neurons of the stomatogastric ganglion. J Neurophysiol 2012; 107:718–727Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byFrom Postmortem Molecular Studies to Social Determinants of Health Relevant to Racial and Ethnic DisparitiesNed H. Kalin, M.D.1 July 2023 | American Journal of Psychiatry, Vol. 180, No. 7 Volume 180Issue 7 July 01, 2023Pages 470-472 Metrics KeywordsSchizophrenia Spectrum and Other Psychotic DisordersCognition/Learning/MemoryPharmacotherapyPDF download History Accepted 15 May 2023 Published online 1 July 2023 Published in print 1 July 2023

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 CaMKII alpha heterozygous mouse (CaMKII alpha-hKO). The current study characterizes behavioral phenotypes of CaMKII alpha-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKII alpha-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 CaMKII alpha-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. CaMKII alpha-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, CaMKII alpha-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, CaMKII alpha-hKO mice likely model a subpopulation of patients with schizophrenia. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Sarcoma tyrosine kinase (Src) is a hub for signaling mechanisms affecting NMDA GluN2 phosphorylation and is disrupted by convergent alterations of various schizophrenia susceptibility pathways. We recently showed reduced mismatch negativity and memory in mice heterozygous for the Src gene (Src+/- mice). Src Associated Protein Interfering Peptide (TAT-SAPIP) is a cell-penetrating peptide that disrupts PSD-95–Src association, increasing Src activity in synaptic membranes and enhancing hippocampal GluN currents. We sought to assess the ability for TAT-SAPIP to reverse cognitive and electrophysiological changes in Src+/- mice.

Recently published studies indicate that the Covid-19 pandemic has dramatically increased rates of anxiety, depression, and suicide in adolescents and young adults. Human and animal studies strongly indicate that early life stress leads to lasting changes to cognition and psychiatric outcomes, but less is known about how chronic adolescent stress may alter brain function across the lifespan.

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.

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.

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.

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 (PVcre/NR1fl/fl) demonstrated altered gamma-band CFC as compared with their control littermates (PVcre/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. PVcre/NR1fl/fl mice exhibited an increase in resting power specific to the high gamma-band, but not other frequency bands, as compared with PVcre/NR1+/+. CFC analyses then examined both the standard magnitude (strength) of CFC and the novel metric PhaseMax-which denotes the phase of the lower frequency signal at which the peak higher frequency signal power occurred. PVcre/NR1fl/fl mice exhibited altered PhaseMax, but not strength, of gamma-band CFC as compared with PVcre/NR1+/+ mice. As such, this study suggests a potential novel metric to explore when studying neuropsychiatric disorders.

The negative symptoms remain among the most disabling and treatment refractory issues for people with schizophrenia Gap: Animal models of the negative symptoms of schizophrenia have been particularly challenging due to a dearth of manipulations with face or construct validity. Additionally, the lack of effective treatments for social and motivational deficits has impaired the ability to assess positive predictive validity from preclinical to clinical application. Despite these limitations, several lines of investigation suggest that alterations of N-Methyl D-Aspartate receptor-mediated glutamate transmission is related to negative symptoms.

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.

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 nonsocial 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.