Nicotine inhalant via E-cigarette facilitates sensorimotor function recovery by upregulating neuronal BDNF-TrkB signalling in traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes. EXPERIMENTAL APPROACH: Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation. KEY RESULTS: Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation. CONCLUSIONS AND IMPLICATIONS: Post-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

A Novel Simple ImmunoAssay for Quantification of Blood Anti-NMDAR1 Autoantibodies.

High titers of anti-NMDAR1 autoantibodies in human brain cause anti-NMDAR1 encephalitis, a rare disease that displays a variety of psychiatric symptoms and neurological symptoms. Currently, immunohistochemical staining and cell-based assays are the standard methods for detection and semi-quantification of the anti-NMDAR1 autoantibodies. Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background from less diluted serum/plasma. Development of a new method to quantify these low titers of blood anti-NMDAR1 autoantibodies is necessary to understand their potential impacts on psychiatric symptoms and cognition. Based on our previous One-Step assay, we report the development of a novel simple immunoassay to quantify cross-species blood anti-NMDAR1 autoantibodies, and its validation with immunohistochemistry and cell-based assays in both humans and mice.

Postnatal Phencyclidine-Induced Deficits in Decision Making Are Ameliorated by Optogenetic Inhibition of Ventromedial Orbitofrontal Cortical Glutamate Neurons.

Background: The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making. Methods: Male and female Wistar rats (n = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning. Results: Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin). Conclusions: Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.

The Relevance of Animal Models of Social Isolation and Social Motivation for Understanding Schizophrenia: Review and Future Directions.

BACKGROUND AND HYPOTHESES: Social dysfunction in schizophrenia includes symptoms of withdrawal and deficits in social skills, social cognition, and social motivation. Based on the course of illness, with social withdrawal occurring prior to psychosis onset, it is likely that the severity of social withdrawal/isolation contributes to schizophrenia neuropathology. STUDY DESIGN: We review the current literature on social isolation in rodent models and provide a conceptual framework for its relationship to social withdrawal and neural circuit dysfunction in schizophrenia. We next review preclinical tasks of social behavior used in schizophrenia-relevant models and discuss strengths and limitations of existing approaches. Lastly, we consider new effort-based tasks of social motivation and their potential for translational studies in schizophrenia. STUDY RESULTS: Social isolation rearing in rats produces profound differences in behavior, pharmacologic sensitivity, and neurochemistry compared to socially reared rats. Rodent models relevant to schizophrenia exhibit deficits in social behavior as measured by social interaction and social preference tests. Newer tasks of effort-based social motivation are being developed in rodents to better model social motivation deficits in neuropsychiatric disorders. CONCLUSIONS: While experimenter-imposed social isolation provides a viable experimental model for understanding some biological mechanisms linking social dysfunction to clinical and neural pathology in schizophrenia, it bypasses critical antecedents to social isolation in schizophrenia, notably deficits in social reward and social motivation. Recent efforts at modeling social motivation using effort-based tasks in rodents have the potential to quantify these antecedents, identify models (eg, developmental, genetic) that produce deficits, and advance pharmacological treatments for social motivation.

Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model.

Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

In vivo mapping of protein-protein interactions of schizophrenia risk factors generates an interconnected disease network.

Genetic analyses of Schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided strong evidence that disrupted PPI networks underlie SCZ pathogenesis. In this study, we performed in vivo PPI analysis of several SCZ risk factors in the rodent brain. Using endogenous antibody immunoprecipitations coupled to mass spectrometry (MS) analysis, we constructed a SCZ network comprising 1612 unique PPI with a 5% FDR. Over 90% of the PPI were novel, reflecting the lack of previous PPI MS studies in brain tissue. Our SCZ PPI network was enriched with known SCZ risk factors, which supports the hypothesis that an accumulation of disturbances in selected PPI networks underlies SCZ. We used Stable Isotope Labeling in Mammals (SILAM) to quantitate phencyclidine (PCP) perturbations in the SCZ network and found that PCP weakened most PPI but also led to some enhanced or new PPI. These findings demonstrate that quantitating PPI in perturbed biological states can reveal alterations to network biology.

Improving Students' Knowledge and Skills Through a Tele-ICU Clinical Rotation.

BACKGROUND: In the course of their education, respiratory therapy students participate in clinical rotations, which are essential to their education. Recently, the number of clinical sites has decreased as some have been eliminated. During the COVID-19 pandemic, schools were challenged to find hospitals to accommodate students due to the risk of infection. Tele-ICU has emerged as a means for staff therapists to assess and monitor patients via remote monitoring systems. We hypothesized that a clinical rotation at a tele-ICU would strengthen students' knowledge of mechanical ventilation, telemedicine, and COVID-19. METHODS: In this study, students completed clinical rotations in a tele-ICU. Students spent two 4-h clinical rotations rounding on 320 ICU beds at 5 hospitals. Under the supervision of experienced therapists, students performed remote patient-ventilator assessments, including review and interpretation of ventilator waveforms, patient-ventilator interaction, arterial blood gases, and chest x-rays. Students completed pre- and post-rotation surveys assessing their confidence managing mechanical ventilation, experience with telemedicine, ARDS, and patients with COVID-19. RESULTS: Mean self-confidence in mechanical ventilation (P = .001), assessing waveforms (P = .001), and knowledge of ARDS increased after the clinical rotation (P = .001). Similarly, reported knowledge related to spontaneous breathing trial protocols (P = .009), lung-protective ventilation (P = .002), patient care planning (P = .001), and use of Excel spreadsheets (P = .002) increased from the beginning to the end of the clinical rotation. Student confidence in interprofessional communication increased from 85 [69-98] to 95 [78-100]; P = .03). Overall, the largest change was students' ability to assess patients with COVID-19 (pre-rotation 50.0 [11.5-65.7], post-rotation 80.0 [58.5-100]; P = .001). Qualitative results revealed overwhelmingly positive results for both students and preceptors. CONCLUSIONS: Students' confidence in assessing patients via remote monitoring increased in a tele-ICU clinical rotation. Self-assessed knowledge related to COVID-19 also increased to statistical significance.

Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

MicroPET evidence for a hypersensitive neuroinflammatory profile of gp120 mouse model of HIV.

Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive deficits persist. Determining biological mechanism(s) underlying abnormalities is critical to minimize the long-term impact of HIV. Positron emission tomography (PET) studies reveal that PLWH exhibit elevated neuroinflammation, potentially contributing to these problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV entry into a cell contributing to HIV-related neurotoxicity. In vivo evidence for mice overexpressing gp120 (transgenic) mice exhibiting neuroinflammation remains unclear. Here, we conducted microPET imaging in gp120 transgenic and wildtype mice, using the radiotracer [(18)F]FEPPA (binds to the translocator protein expressed by activated microglial serving as a neuroinflammatory marker). Imaging was performed at baseline and 24 h after lipopolysaccharide (LPS; 5 mg/kg) treatment (endotoxin that triggers an immune response). Gp120 transgenic mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus. Gp120 transgenic mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or sensitive to any treatments.

C-Reactive Protein: Marker of risk for post-traumatic stress disorder and its potential for a mechanistic role in trauma response and recovery.

Increasing evidence indicates that inflammation plays a role in PTSD and stress disorder pathophysiology. PTSD is consistently associated with higher circulating inflammatory protein levels. Rodent models demonstrate that inflammation promotes enduring avoidance and arousal behaviors after severe stressors (e.g., predator exposure and social defeat), suggesting that inflammation may play a mechanistic role in trauma disorders. C-reactive protein (CRP) is an innate acute phase reactant produced by the liver after acute infection and chronic disease. A growing number of investigations report associations with PTSD diagnosis and elevated peripheral CRP, CRP gene mutations, and CRP gene expression changes in immune signaling pathways. CRP is reasonably established as a potential marker of PTSD and trauma exposure, but if and how it may play a mechanistic role is unclear. In this review, we discuss the current understanding of immune mechanisms in PTSD with a particular focus on the innate immune signaling factor, CRP. We found that although there is consistent evidence of an association of CRP with PTSD symptoms and risk, there is a paucity of data on how CRP might contribute to CNS inflammation in PTSD, and consequently, PTSD symptoms. We discuss potential mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other innate immune signaling factors in modulating trauma responses. Overall, we found that CRP likely contributes to central inflammation, but how it does so is an area for further study.

A thematic analysis of smokers' and non-smokers' accounts of E-cigarettes.

This study explored smokers' and non-smokers' accounts of E-cigarettes. A total of 51 UK-based participants, 20 men and 31 women, responded to open-ended questions online. Inductive thematic analysis identified that the factors that influence E-cigarette behaviour and opinion in adult smokers and non-smokers are related to social context, informative sources, practical aspects and health implications. Participants presented varying accounts of E-cigarettes, suggesting that individual narratives regarding E-cigarettes are multi-faceted. This is important information for health professionals and policy makers tasked with advising on E-cigarette use.

An investigation of factors encouraging and deterring EC use: a thematic analysis of accounts from UK adults.

OBJECTIVE: This study aimed to explore E-cigarette (EC) accounts from a small sample of UK adults with varied smoking/EC experiences. This was to contribute to existing knowledge of adult perceptions and understand the factors that encourage or deter use to inform health messaging aimed at professionals, policy makers and the general public. DESIGN: Twelve participants, five men and seven women aged 23-55 years (mean age 32.43) with mixed smoking/EC backgrounds took part in face-to-face interviews, analysed using semantic-level inductive thematic analysis. RESULTS: The analysis identified three key themes. Social influence (1) relates to the understanding of the social representations of ECs. Representation and knowledge (2) captures the impact of varied EC related communication on perception. Aspects of addiction (3) conveys aspects of nicotine addiction and how this influences EC use. CONCLUSION: ECs were generally perceived as more socially acceptable than cigarettes by non-smokers, although there were varying levels of acceptability depending on the type of EC device used. There was also unanimity concerning uncertainty surrounding the devices. Behavioural/sensory elements and personal enjoyment of ECs were consistent elements that encouraged or deterred use. Although non-smokers/vapers did not use the devices, they expressed similar apprehensions to those who did.

Evaluation of neurotoxicity and long-term function and behavior following intrathecal 1 % 2-chloroprocaine in juvenile rats.

Spinally-administered local anesthetics provide effective perioperative anesthesia and/or analgesia for children of all ages. New preparations and drugs require preclinical safety testing in developmental models. We evaluated age-dependent efficacy and safety following 1 % preservative-free 2-chloroprocaine (2-CP) in juvenile Sprague-Dawley rats. Percutaneous lumbar intrathecal 2-CP was administered at postnatal day (P)7, 14 or 21. Mechanical withdrawal threshold pre- and post-injection evaluated the degree and duration of sensory block, compared to intrathecal saline and naive controls. Tissue analyses one- or seven-days following injection included histopathology of spinal cord, cauda equina and brain sections, and quantification of neuronal apoptosis and glial reactivity in lumbar spinal cord. Following intrathecal 2-CP or saline at P7, outcomes assessed between P30 and P72 included: spinal reflex sensitivity (hindlimb thermal latency, mechanical threshold); social approach (novel rat versus object); locomotor activity and anxiety (open field with brightly-lit center); exploratory behavior (rearings, holepoking); sensorimotor gating (acoustic startle, prepulse inhibition); and learning (Morris Water Maze). Maximum tolerated doses of intrathecal 2-CP varied with age (1.0 µL/g at P7, 0.75 µL/g at P14, 0.5 µL/g at P21) and produced motor and sensory block for 10-15 min. Tissue analyses found no significant differences across intrathecal 2-CP, saline or naïve groups. Adult behavioral measures showed expected sex-dependent differences, that did not differ between 2-CP and saline groups. Single maximum tolerated in vivo doses of intrathecal 2-CP produced reversible spinal anesthesia in juvenile rodents without detectable evidence of developmental neurotoxicity. Current results cannot be extrapolated to repeated dosing or prolonged infusion.

Exploring Trends and Differences in Health Behaviours of Health Sciences University Students from Germany and England: Findings from the "SuSy" Project.

Objectives: This research aimed to explore the health behaviours of health sciences students over time and across different settings. Methods: A health behaviour surveillance system has been implemented in Hamburg and Manchester among under- and postgraduate health sciences students. Trends among the Hamburg sample were described. In a cross-sectional assessment, health behaviours across both universities were examined using multivariate regression analysis. Results: Between 2014 and 2018, increasing trends in physical activity and cannabis and alcohol consumption were observed in Hamburg (n = 1,366). While fruit and vegetable intake was constantly low, tobacco smoking decreased. No clear trend was observed for stress perception. The comparison (n = 474) revealed that Manchester students had higher odds of smoking, excessive alcohol consumption, and fruit and vegetable consumption; and lower odds of being physically active, and consuming cannabis. No difference in stress perception was observed. Conclusions: Varying trends and potential areas of intervention were identified for health behaviours in Hamburg. The comparison with Manchester students revealed differences in behaviours, which could be further explored to help inform health promotion strategies in both settings.

Chronic presence of blood circulating anti-NMDAR1 autoantibodies impairs cognitive function in mice.

High titers of anti-NMDAR1 autoantibodies in brain cause anti-NMDAR1 encephalitis that displays psychiatric symptoms of schizophrenia and/or other psychiatric disorders in addition to neurological symptoms. Low titers of anti-NMDAR1 autoantibodies are reported in the blood of a subset of the general human population and psychiatric patients. Since ~0.1-0.2% of blood circulating antibodies cross the blood-brain barriers and antibodies can persist for months and years in human blood, it is important to investigate whether chronic presence of these blood circulating anti-NMDAR1 autoantibodies may impair human cognitive functions and contribute to the development of psychiatric symptoms. Here, we generated mice carrying low titers of anti-NMDAR1 autoantibodies in blood against a single antigenic epitope of mouse NMDAR1. Mice carrying the anti-NMDAR1 autoantibodies are healthy and display no differences in locomotion, sensorimotor gating, and contextual memory compared to controls. Chronic presence of the blood circulating anti-NMDAR1 autoantibodies, however, is sufficient to impair T-maze spontaneous alternation in the integrity of blood-brain barriers across all 3 independent mouse cohorts, indicating a robust cognitive deficit in spatial working memory and/or novelty detection. Our studies implicate that chronic presence of low titers of blood circulating anti-NMDAR1 autoantibodies may impair cognitive functions in both the general healthy human population and psychiatric patients.

Dissociable impact of childhood trauma and deployment trauma on affective modulation of startle.

Trauma disorders are often associated with alterations in aversive anticipation and disruptions in emotion/fear circuits. Heightened or blunted anticipatory responding to negative cues in adulthood may be due to differential trauma exposure during development, and previous trauma exposure in childhood may also modify effects of subsequent trauma in adulthood. The aim of the current investigation was to examine the contributions of childhood trauma on affective modulation of startle before and after trauma exposure in adulthood (a combat deployment). Adult male participants from the Marine Resilience Study with (n = 1145) and without (n = 1312) a history of reported childhood trauma completed an affective modulation of startle task to assess aversive anticipation. Affective startle response was operationalized by electromyography (EMG) recording of the orbicularis oculi muscle in response to acoustic stimuli when anticipating positive and negative affective images. Startle responses to affective images were also assessed. Testing occurred over three time-points; before going on a 7 month combat deployment and 3 and 6 months after returning from deployment. Startle response when anticipating negative images was greater compared to pleasant images across all three test periods. Across all 3 time points, childhood trauma was consistently associated with significantly blunted startle when anticipating negative images, suggesting reliable effects of childhood trauma on aversive anticipation. Conversely, deployment trauma was associated with increased startle reactivity post-deployment compared to pre-deployment, which was independent of childhood trauma and image valence. These results support the hypothesis that trauma exposure during development vs. adulthood may have dissociable effects on aversive anticipation and arousal mechanisms. Further study in women and across more refined age groups is needed to test generalizability and identify potential developmental windows for these differential effects.

Scalable modEls of Community rehAbilitation for Individuals Recovering From COVID:19 reLated illnEss: A Longitudinal Service Evaluation Protocol-"SeaCole Cohort Evaluation".

Introduction: High levels of physical, cognitive, and psychosocial impairments are anticipated for those recovering from the COVID-19. In the UK, ~50% of survivors will require additional rehabilitation. Despite this, there is currently no evidence-based guideline available in England and Wales that addresses the identification, timing and nature of effective interventions to manage the morbidity associated following COVID-19. It is now timely to accelerate the development and evaluation of a rehabilitation service to support patients and healthcare services. Nuffield Health have responded by configuring a scalable rehabilitation pathway addressing the immediate requirements for those recovering from COVID-19 in the community. Methods and Analysis: This long-term evaluation will examine the effectiveness of a 12-week community rehabilitation programme for COVID-19 patients who have been discharged following in-patient treatment. Consisting of two distinct 6-week phases; Phase 1 is an entirely remote service, delivered via digital applications. Phase 2 sees the same patients transition into a gym-based setting for supervised group-based rehabilitation. Trained rehabilitation specialists will coach patients across areas such as goal setting, exercise prescription, symptom management and emotional well-being. Outcomes will be collected at 0, 6, and 12 weeks and at 6- and 12-months. Primary outcome measures will assess changes in health-related quality of life (HR-QOL) and COVID-19 symptoms using EuroQol Five Dimension Five Level Version (EQ-5D-5L) and Dyspnea-12, respectively. Secondary outcome measures of the Duke Activity Status Questionnaire (DASI), 30 s sit to stand test, General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Patient Experience Questionnaire (PEQ) and Quality Adjusted Life Years (QALY) will allow for the evaluation of outcomes, mediators and moderators of outcome, and cost-effectiveness of treatment. Discussion: This evaluation will investigate the immediate and long-term impact, as well as the cost effectiveness of a blended rehabilitation programme for COVID-19 survivors. This evaluation will provide a founding contribution to the literature, evaluating one of the first programmes of this type in the UK. The evaluation has international relevance, with the potential to show how a new model of service provision can support health services in the wake of COVID-19. Trial Registration: Current Trials ISRCTN ISRCTN14707226 Web: http://www.isrctn.com/ISRCTN14707226.

GRK3 deficiency elicits brain immune activation and psychosis.

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1ß, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.