Epigenetic Regulation in Schizophrenia: Focus on Methylation and Histone Modifications in Human Studies.

Despite extensive research over the last few decades, the etiology of schizophrenia (SZ) remains unclear. SZ is a pathological disorder that is highly debilitating and deeply affects the lifestyle and minds of those affected. Several factors (one or in combination) have been reported as contributors to SZ pathogenesis, including neurodevelopmental, environmental, genetic and epigenetic factors. Deoxyribonucleic acid (DNA) methylation and post-translational modification (PTM) of histone proteins are potentially contributing epigenetic processes involved in transcriptional activity, chromatin folding, cell division and apoptotic processes, and DNA damage and repair. After establishing a summary of epigenetic processes in the context of schizophrenia, this review aims to highlight the current understanding of the role of DNA methylation and histone PTMs in this disorder and their potential roles in schizophrenia pathophysiology and pathogenesis.

Perceived Parent Needs for Improving Parent Participation in School-Based Therapies for Children with Disabilities Using the Parent-Therapist Partnership Survey.

Rehabilitative and habilitative therapies can help children with disabilities increase independence and overall wellbeing. However, children and their caregivers face many barriers to accessing these therapies and often rely on the school for therapy access. Given the limited resources available within the special education system, increasing parent involvement in special education therapies could improve service delivery. However, providers must first understand what parents need to participate in therapies before attempting to engage families. 217 parents completed an online survey consisting of the Parent-Therapist Partnership Survey and demographic questionnaires about theirfamiliesand their child[ren] with disabilities. The percentage of needs parents endorsed as important and thepercentageofimportantneedsendorsedasunmetwere calculated. Differences across demographic variables were assessed. Overall, parents reported an average of 75% of needs as important with significantly more needs endorsed as important regarding being an informed, engaged member of the child's care team (M = 83%) than needs related to support and guidance (M = 65%, p < 0.001). Furthermore, parentsreportedan average of 58% of important needs as unmet, with no significant differences in subscale averages. Significant associations were found for race/ethnicity, education, income, partner availability, number of children with disabilities in the household, transportation access, neighborhood opportunities, parent efficacy and social, emotional, and behavioral concerns. Parents reported a high percentage of needs as important, but a large percentage of these important needs were considered unmet. Significant disparities based on racial/ethnic identities and access to resources were found. In order to successfully engage parents in special education therapy activities, providers must work to understand and address parents' engagement needs, paying special attention to each family's unique circumstances to optimize engagement.

Genetic and Epigenetic Regulation in Lingo-1: Effects on Cognitive Function and White Matter Microstructure in a Case-Control Study for Schizophrenia.

Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3'-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016-1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology.

Parent-Perceived Benefits and Harms Associated With Internet Use by Adolescent Offspring.

Importance: Limited systematic information on familial factors and perception of the benefits and harms of internet use by youths is available. Much of the current research has been hampered by small nondiverse samples and limited information on key familial and offspring characteristics. Objective: To characterize parental perceptions and concerns about internet use associated with adolescent development, well-being, safety, family connectedness, and potential for problematic internet use. Design, Setting, and Participants: A 20-minute, English-language survey was developed with expert stakeholders using previously validated questionnaires and was conducted online between June 17 and July 5, 2022. Participants included 1005 parents of children and adolescents aged 9 to 15 years drawn from an online digital survey platform and calibrated for representation with post hoc weightings. Main Outcomes and Measures: Parent survey responses about family characteristics and internet use were used to compute Internet Addiction Test scores for parents and their offspring, Alabama Parenting Questionnaire scores, and an aggregate family connectedness score. Results: The survey cohort of 1005 parents included 568 women (56.5%) and 437 men (43.5%) with a mean age (SD) of 39.5 (6.4) years. In terms of race and ethnicity, the most common categories included Black or African American (95 [9.5%]), Latinx or Hispanic (100 [10.0%]), White (602 [59.9%]), and 2 or more races or ethnicities (122 [12.1%]). Respondents endorsed parental concerns that included exposure to harmful content (646 [64.3%]) and online bullying (533 [53.0%]). Two hundred twenty-five parents (22.4%) had specific concerns about internet addiction in their adolescent offspring, and twice as many parents reported specific concerns about internet addiction than substance addiction. However, parents also indicated that internet use improved family connectedness among immediate families (468 [46.6%]) and extended families (568 [56.5%]). Internet Addiction Test scores in adolescent offspring were correlated with parent scores (ß = 0.62 [SE = 0.02]; P < .001) and Alabama Parenting Questionnaire-Inconsistent Discipline scores (ß = 0.23 [SE = 0.11]; P = .04). Conclusions and Relevance: In this survey study of parent perceptions of internet use among adolescent offspring, parents believed the internet brought families closer yet also expressed concerns. Problematic internet use among youths was correlated with negative parenting styles and parent internet use. This research adds to the literature by suggesting that families, their communities, and industry may have common ground to collaborate on reducing the negative effects of internet use.

Can Genetic Markers Predict the Sporadic Form of Alzheimer's Disease? An Updated Review on Genetic Peripheral Markers.

Alzheimer's disease (AD) is the most common form of dementia that affects millions of individuals worldwide. Although the research over the last decades has provided new insight into AD pathophysiology, there is currently no cure for the disease. AD is often only diagnosed once the symptoms have become prominent, particularly in the late-onset (sporadic) form of AD. Consequently, it is essential to further new avenues for early diagnosis. With recent advances in genomic analysis and a lower cost of use, the exploration of genetic markers alongside RNA molecules can offer a key avenue for early diagnosis. We have here provided a brief overview of potential genetic markers differentially expressed in peripheral tissues in AD cases compared to controls, as well as considering the changes to the dynamics of RNA molecules. By integrating both genotype and RNA changes reported in AD, biomarker profiling can be key for developing reliable AD diagnostic tools.

Sulfation Pathways During Neurodevelopment.

Sulfate is an important nutrient that modulates a diverse range of molecular and cellular functions in mammalian physiology. Over the past 2 decades, animal studies have linked numerous sulfate maintenance genes with neurological phenotypes, including seizures, impaired neurodevelopment, and behavioral abnormalities. Despite sulfation pathways being highly conserved between humans and animals, less than one third of all known sulfate maintenance genes are clinically reportable. In this review, we curated the temporal and spatial expression of 91 sulfate maintenance genes in human fetal brain from 4 to 17 weeks post conception using the online Human Developmental Biology Resource Expression. In addition, we performed a systematic search of PubMed and Embase, identifying those sulfate maintenance genes linked to atypical neurological phenotypes in humans and animals. Those findings, together with a search of the Online Mendelian Inheritance in Man database, identified a total of 18 candidate neurological dysfunction genes that are not yet considered in clinical settings. Collectively, this article provides an overview of sulfate biology genes to inform future investigations of perturbed sulfate homeostasis associated with neurological conditions.

Associations between Omega-3 Index, Dopaminergic Genetic Variants and Aggressive and Metacognitive Traits: A Study in Adult Male Prisoners.

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are critical for cell membrane structure and function. Human beings have a limited ability to synthesise docosahexaenoic acid (DHA), the main n-3 LCPUFA required for neurological development. Inadequate levels of n-3 LCPUFA can affect the dopaminergic system in the brain and, when combined with genetic and other factors, increase the risk of developing aggression, inattention and impulse-control disorders. In this study, male prisoners were administered questionnaires assessing aggressive behaviour and executive functions. Participants also produced blood sampling for the measurement of the Omega-3 Index and the genotyping of dopaminergic genetic variants. Significant associations were found between functional genetic polymorphism in DBH rs1611115 and verbal aggression and between DRD2 rs4274224 and executive functions. However, the Omega-3 Index was not significantly associated with the tested dopaminergic polymorphisms. Although previous interactions between specific genotypes and n-3 LCPUFA were previously reported, they remain limited and poorly understood. We did not find any association between n-3 LCPUFA and dopaminergic polymorphisms in adult male prisoners; however, we confirmed the importance of genetic predisposition for dopaminergic genes (DBH and DRD2) in aggressive behaviour, memory dysfunction and attention-deficit disorder.

Not all stress is created equal: Acute, not ambient stress, impairs learning in high schizotypes.

Learning from feedback is essential for daily functioning, with factors that impact learning having implications for healthy and clinical populations. Reinforcement learning appears impaired across the psychosis continuum, with deficits reported in patients with psychotic disorders as well as high schizotypes from the general population. Stress can impair learning, and sensitivity to stress is present along the psychosis continuum. The aim of the present study was to understand if stress impairs reinforcement learning in those at the lower end of the psychosis continuum. We investigated both naturalistic stress in everyday life using daily hassles (Study 1: n = 70; 31% male, M age = 22.67 years) and acute psychosocial stress using the Trier Social Stress Test (Study 2: n = 57; 32% male, M age = 22.43 years). In the presence of naturalistic stress, learning did not differ across schizotypes. However, under acute psychosocial stress, high schizotypes experienced impaired learning. Our results suggest trail-and-error learning is robust to the ebbs and flows of everyday stress for high schizotypes; however, acute stress is associated with decrements in learning. This indicates that the magnitude of stressors should be considered when designing cognitive and functional interventions for those along the psychosis continuum.

A memory-driven auditory program ensures selective and precise vocal imitation in zebra finches.

In the vocal learning model, the juvenile first memorizes a model sound, and the imprinted memory gradually converts into vocal-motor output during the sensorimotor integration. However, early acquired memory may not precisely represent the fine structures of a model sound. How do juveniles ensure precise model imitation? Here we show that juvenile songbirds develop an auditory learning program by actively and attentively engaging with tutor's singing during the sensorimotor phase. The listening/approaching behavior requires previously acquired model memory and the individual variability of approaching behavior correlates with the precision of tutor song imitation. Moreover, it is modulated by dopamine and associated with forebrain regions for sensory processing. Overall, precise vocal learning may involve two steps of auditory processing: a passive imprinting of model memory occurs during the early sensory period; the previously acquired memory then guides an active and selective engagement of the re-exposed model to fine tune model imitation.

The effect of omega-3 long chain polyunsaturated fatty acids on aggressive behaviour in adult male prisoners: a structured study protocol for a multi-centre, double-blind, randomised placebo-controlled trial and translation into policy and practice.

BACKGROUND: Interventions to better manage aggressive behaviour and reduce recidivism are a primary concern for corrective services. Nutritional interventions to correct prisoner behaviour have been largely overlooked in the literature. Emerging evidence suggests that dietary intake influences aggressive behaviours and that nutritional supplementation with omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) could attenuate both the severity and frequency of aggressive behaviour. METHODS: Adult male prisoners who have a history of aggressive behaviour (n = 600) will be recruited from at least 6 Correctional Centres and randomised to receive either n-3 LCPUFA or placebo supplementation for a 16-week duration. Treatment will be with either 1 g/day of n-3 LCPUFA (694 mg DHA and 397 mg EPA) or placebo capsules, which are a corn/soy oil blend and are identical in size and colour. The primary outcome measure is the Inmate Behavioural Observation Scale (IBOS): an objective measure of aggressive behaviour. Secondary outcome measures include questionnaires (including aggression, attention deficit disorder, impulsivity, depression/anxiety/stress scales), engagement in programmes, recidivism and quality of life. Baseline and post-intervention assessments include the IBOS, questionnaires and blood to measure the levels of n-3 LCPUFA. DISCUSSION: To conclusively test the potential that increasing n-3 LCPUFA intakes can improve rates of prisoner aggression and associated mental health and violence-related social system management costs, we propose an adequately powered multi-centre, double-blind, randomised controlled trial, examining the effects of n-3 LCPUFA supplementation on aggressive behaviour in adult male prisoners. If successful, this study will inform prisoner policy with respect to nutrition and by inference contribute to a broader community approach to preventative mental health practices. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN12618001665224 . Registered on 10 October 2018.

Exploring new avenues for modifying course of progression of Alzheimer's disease: The rise of natural medicine.

With a constantly growing elderly population worldwide, a focus on developing efficient prevention and therapy for Alzheimer's disease (AD) seems timely and topical. Emphasis on natural medicine is increasingly popular in the search for drug candidates that are capable of preventing and treating AD related pathology, particularly where suppression of amyloid accumulation, neurofibrillary tangle formation, neuroinflammation and oxidative stress are equally significant. A number of phytochemical compounds have been shown to collectively reduce these AD hallmarks with the progression of natural drug candidates into human clinical trials. This review focuses on current research surrounding the therapies emerging within natural medicines and their related therapeutic potential for AD treatment.

The effects of perinatal fluoxetine exposure on emotionality behaviours and cortical and hippocampal glutamatergic receptors in female Sprague-Dawley and Wistar-Kyoto rats.

RATIONALE: There is increasing concern regarding the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy. Animal studies repeatedly show increased anxiety- and depressive-like behaviours in offspring exposed perinatally to SSRIs, however much of this research is in male offspring. OBJECTIVES: The primary aim of this study was to investigate the effects of perinatal SSRI exposure on emotionality-related behaviours in female offspring and associated glutamatergic markers, in Sprague-Dawley (SD) rats and in the Wistar-Kyoto (WKY) rat model of depression. Secondly, we sought to investigate the glutamatergic profile of female WKY rats that may underlie their depressive- and anxiety-like phenotype. METHODS: WKY and SD rat dams were treated with the SSRI, fluoxetine (FLX; 10 mg/kg/day), or vehicle, throughout gestation and lactation (5 weeks total). Female adolescent offspring underwent behaviour testing followed by quantitative immunoblot of glutamatergic markers in the prefrontal cortex and ventral hippocampus. RESULTS: Naïve female WKY offspring displayed an anxiety-like and depressive-like phenotype as well as reductions in NMDA and AMPA receptor subunits and PSD-95 in both ventral hippocampus and prefrontal cortex, compared to SD controls. Perinatal FLX treatment increased anxiety-like and forced swim immobility behaviours in SD offspring but did not influence behaviour in female WKY offspring using these tests. Perinatal FLX exposure did not influence NMDA or AMPA receptor subunit expression in female WKY or SD offspring; it did however have restricted effects on group I mGluR expression in SD and WKY offspring and reduce the glutamatergic synaptic scaffold, PSD-95. CONCLUSION: These findings suggest female offspring of the WKY strain display deficits in glutamatergic markers which may be related to their depressive- and anxiety-like phenotype. While FLX exposed SD offspring displayed increases in anxiety-like and depressive-like behaviours, further studies are needed to assess the potential impact of developmental FLX exposure on the behavioural phenotype of female WKY rats.

Electrophysiological correlates of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism.

The brain-derived neurotrophic factor (BDNF) protein is essential for neuronal development. Val66Met (rs6265) is a functional polymorphism at codon 66 of the BDNF gene that affects neuroplasticity and has been associated with cognition, brain structure and function. The aim of this study was to clarify the relationship between BDNF Val66Met polymorphism and neuronal oscillatory activity, using the electroencephalogram (EEG), in a normative cohort. Neurotypical (N = 92) young adults were genotyped for the BDNF Val66Met polymorphism and had eyes open resting-state EEG recorded for four minutes. Focal increases in right fronto-parietal delta, and decreases in alpha-1 and right hemispheric alpha-2 amplitudes were observed for the Met/Met genotype group compared to Val/Val and Val/Met groups. Stronger frontal topographies were demonstrated for beta-1 and beta-2 in the Val/Met group versus the Val/Val group. Findings highlight BDNF Val66Met genotypic differences in EEG spectral amplitudes, with increased cortical excitability implications for Met allele carriers.

Oxidative stress in alzheimer's disease: A review on emergent natural polyphenolic therapeutics.

OBJECTIVES: The aim of this research was to review the literature on Alzheimer's disease (AD) with a focus on polyphenolics as antioxidant therapeutics. DESIGN: This review included a search of the literature up to and including September 2019 in PubMed and MEDLINE databases using search terms that included: Alzheimer's Disease, Aß peptide, tau, oxidative stress, redox, oxidation, therapeutic, antioxidant, natural therapy, polyphenol. Any review articles, case studies, research reports and articles in English were identified and subsequently interrogated. Citations within relevant articles were also examined for consideration in this review. RESULTS: Alzheimer's disease is a neurodegenerative disorder that is clinically characterised by the progressive deterioration of cognitive functions and drastic changes in behaviour and personality. Due to the significant presence of oxidative damage associated with abnormal Aß accumulation and neurofibrillary tangle deposition in AD patients' brains, antioxidant drug therapy has been investigated as potential AD treatment. In particular, naturally occurring compounds, such as plant polyphenols, have been suggested to have potential neuroprotective effects against AD due to their diverse array of physiological actions, which includes potent antioxidant effects. CONCLUSIONS: The impact of oxidative stress and various mechanisms of pathogenesis in AD pathophysiology was demonstrated along with the therapeutic potential of emergent antioxidant drugs to address such mechanism of oxidation.

Perinatal exposure to fluoxetine increases anxiety- and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression.

BACKGROUND: With approximately 10% of pregnant women prescribed antidepressant drugs for the treatment of depressive disorders, there is growing concern regarding the potential long-term effects of this exposure on offspring. Research is needed in clinically relevant models to determine the effects on offspring behaviour and associated neurobiological systems. AIM: The aim of this study was to determine the effects of maternal fluoxetine treatment on anxiety-like and depressive-like behaviours in adolescent offspring as well as associated glutamatergic markers, using a clinically relevant rodent model of depression. METHODS: Wistar-Kyoto (model of innate depression) and Sprague-Dawley rats were treated with fluoxetine (10 mg/kg) from gestational day 0 to postnatal day 14. Male offspring underwent behavioural testing (open field, elevated plus maze, forced swim test) at adolescence followed by quantitative immuno-detection of glutamatergic markers in the prefrontal cortex and ventral hippocampus. RESULTS: Perinatal fluoxetine exposure exacerbated the anxiety-like and depressive-like phenotype in Wistar-Kyoto offspring and induced an anxiety-like and depressive-like phenotype in Sprague-Dawley offspring. Wistar-Kyoto offspring showed reductions in NMDA receptor NR1, NR2A and NR2B subunits, as well as post-synaptic density 95 (PSD-95) and metabotropic glutamate receptor subtype 1 (mGluR1) in the prefrontal cortex; perinatal fluoxetine exposure further reduced NR1, NR2A, PSD-95 and mGluR1 expression in Wistar-Kyoto as well as Sprague-Dawley offspring. In the ventral hippocampus perinatal fluoxetine exposure reduced PSD-95 and increased metabotropic glutamate receptor subtype 5 (mGluR5) and Homer1b/c in both Sprague-Dawley and Wistar-Kyoto strains. CONCLUSION: These findings suggest that maternal fluoxetine treatment exacerbates effects of underlying maternal depression on offspring behaviour, which may be mediated through alterations in the glutamatergic system. Further research investigating how to minimise these effects, whilst ensuring optimal treatment for mothers, is essential to move the field forward.

Interrogating the Relationship Between Schizotypy, the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism, and Neuronal Oscillatory Activity.

The COMT Val158Met polymorphism affects the availability of synaptic dopamine in the prefrontal cortex and has been widely studied as a genetic risk factor for psychosis. Schizotypy is associated with an increased risk of psychosis, with some studies implicating similar neurobiological mechanisms to schizophrenia. The present study sought to interrogate the link between the COMT Val158Met polymorphism and schizotypy using electroencephalogram (EEG) to identify neurophysiological mechanisms underpinning psychosis risk. Neurotypical (N = 91) adults were genotyped for the COMT Val158Met polymorphism, completed the Schizotypal Personality Questionnaire (SPQ), and had eyes open resting-state EEG recorded for 4 min. SPQ suspiciousness subscale scores were higher for individuals homozygous for Val/Val and Met/Met versus Val/Met genotypes. Delta, theta, alpha-2, beta-1, and beta-2 amplitudes were lower for Val/Val than Met/Met individuals. Lower theta amplitudes were correlated with higher total SPQ scores (P = 0.050), and multiple regression revealed that higher delta, and lower theta and beta-2 amplitudes (but not COMT genotype) best predicted total SPQ scores (P = 0.014). This study demonstrates the importance of COMT genotype in determining trait suspiciousness and EEG oscillatory activity. It also highlights relationships between dopaminergic alterations, EEG and schizotypy that are dissimilar to those observed in schizophrenia.

Stress induced cortisol release and schizotypy.

Cortisol is involved in preparing the body's response for stress. However, in those at risk for mental health problems, abnormal cortisol release following stress has been reported. In particular, we are yet to fully understand how stress leads to an exacerbation of symptoms and progression of risk in those who express psychosis proneness or schizotypy. Using the Trier Social Stress Test, we examined the effect of experimentally induced psychosocial stress on cortisol release in otherwise healthy individuals with schizotypal traits. This cross-sectional study included 58 individuals (32.76% male, mean age 22.43). Schizotypy was assessed by total Schizotypal Personality Questionnaire score and we additionally captured ratings of subjective stress. Salivary cortisol was collected over six time points spread prior to and after stress induction and was available for analysis in 39 individuals (28.21% male, mean age 22.77). Those with high schizotypal traits exhibited higher baseline cortisol levels (5.18 nmoL vs 3.71 nmoL). However, those with high schizotypal traits also displayed reduced mean cortisol release (2.02 nmoL vs 5.11 nmoL) and had a delayed cortisol release peak following psychosocial stress. These results indicate those with high schizotypal traits do not display physiological readiness following psychosocial stressors, perhaps due to an already taxed stress system.

Effects of common GRM5 genetic variants on cognition, hippocampal volume and mGluR5 protein levels in schizophrenia.

GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (-12.3%); this effect was exaggerated in males with schizophrenia (-15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.

Perinatal administration of phencyclidine alters expression of Lingo-1 signaling pathway proteins in the prefrontal cortex of juvenile and adult rats.

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague-Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 (P=0.045), and at 14 weeks PCP increased Lingo-1 (P=0.037), TROY (P=0.017), and WNK1 (P=0.003) expression. This is the first study reporting an alteration in Lingo-1 signaling proteins in the rat prefrontal cortex both directly after PCP treatment in early development and in adulthood. We propose that Lingo-1 pathways may be negatively regulating myelination and neurite outgrowth following the administration of PCP, and that this may have implications for the cortical dysfunction observed in schizophrenia.

Genetic Consideration of Schizotypal Traits: A Review.

Schizotypal traits are of interest and importance in their own right and also have theoretical and clinical associations with schizophrenia. These traits comprise attenuated psychotic symptoms, social withdrawal, reduced cognitive capacity, and affective dysregulation. The link between schizotypal traits and psychotic disorders has long since been debated. The status of knowledge at this point is such schizotypal traits are a risk for psychotic disorders, but in and of themselves only confer liability, with other risk factors needing to be present before a transition to psychosis occurs. Investigation of schizotypal traits also has the possibility to inform clinical and research pursuits concerning those who do not make a transition to psychotic disorders. A growing body of literature has investigated the genetic underpinnings of schizotypal traits. Here, we review association, family studies and describe genetic disorders where the expression of schizotypal traits has been investigated. We conducted a thorough review of the existing literature, with multiple search engines, references, and linked articles being searched for relevance to the current review. All articles and book chapters in English were sourced and reviewed for inclusion. Family studies demonstrate that schizotypal traits are elevated with increasing genetic proximity to schizophrenia and some chromosomal regions have been associated with schizotypy. Genes associated with schizophrenia have provided the initial start point for the investigation of candidate genes for schizotypal traits; neurobiological pathways of significance have guided selection of genes of interest. Given the chromosomal regions associated with schizophrenia, some genetic disorders have also considered the expression of schizotypal traits. Genetic disorders considered all comprise a profile of cognitive deficits and over representation of psychotic disorders compared to the general population. We conclude that genetic variations associated with schizotypal traits require further investigation, perhaps with targeted phenotypes narrowed to assist in refining the clinical end point of significance.