Related Neuropsychiatric Disorders Research Articles

40 Hz Steady-State Response in Human Auditory Cortex Is Shaped by GABAergic Neuronal Inhibition.

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, non-invasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under placebo. The GABAA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA-blocker memantine. Our findings indicate that the 40 Hz ASSR in auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA-A receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition.Significance statement The 40 Hz auditory steady-state response is a candidate non-invasive biomarker for schizophrenia and related neuropsychiatric disorders. Yet, the understanding of the synaptic basis of this neurophysiological signature in humans has remained incomplete. We combined magnetoencephalography (MEG) recordings with placebo-controlled pharmacological interventions in healthy human subjects to test the modulation of the 40 Hz ASSR in auditory cortex by two synaptic components that have been implicated in the generation of neuronal oscillations in cortical microcircuits: glutamate N-methyl-aspartate glutamate (NMDA) receptors and gamma-amino-butyric acid (GABA) -A receptors. Boosting GABAergic transmission, but not blocking NMDA-receptors, increased the amplitude of this ASSR. Thus, GABAergic inhibition modulates 40 Hz steady-state responses in auditory cortex.

The Impact of Early-Life Cecal Microbiota Transplantation on Social Stress and Injurious Behaviors in Egg-Laying Chickens.

Injurious behaviors (i.e., aggressive pecking, feather pecking, and cannibalism) in laying hens are a critical issue facing the egg industry due to increased social stress and related health and welfare issues as well as economic losses. In humans, stress-induced dysbiosis increases gut permeability, releasing various neuroactive factors, causing neuroinflammation and related neuropsychiatric disorders via the microbiota-gut-brain axis, and consequently increasing the frequency and intensity of aggression and violent behaviors. Restoration of the imbalanced gut microbial composition has become a novel treatment strategy for mental illnesses, such as depression, anxiety, bipolar disorder, schizophrenia, impulsivity, and compulsivity. A similar function of modulating gut microbial composition following stress challenge may be present in egg-laying chickens. The avian cecum, as a multi-purpose organ, has the greatest bacterial biodiversity (bacterial diversity, richness, and species composition) along the gastrointestinal tract, with vitally important functions in maintaining physiological and behavioral homeostasis, especially during the periods of stress. To identify the effects of the gut microbiome on injurious behaviors in egg-laying chickens, we have designed and tested the effects of transferring cecal contents from two divergently selected inbred chicken lines on social stress and stress-related injurious behaviors in recipient chicks of a commercial layer strain. This article reports the outcomes from a multi-year study on the modification of gut microbiota composition to reduce injurious behaviors in egg-laying chickens. An important discovery of this corpus of experiments is that injurious behaviors in chickens can be reduced or inhibited through modifying the gut microbiota composition and brain serotonergic activities via the gut-brain axis, without donor-recipient genetic effects.

Dopamine transporter blockade during adolescence increases adult dopamine function, impulsivity, and aggression

Sensitive developmental periods shape neural circuits and enable adaptation. However, they also engender vulnerability to factors that can perturb developmental trajectories. An understanding of sensitive period phenomena and mechanisms separate from sensory system development is still lacking, yet critical to understanding disease etiology and risk. The dopamine system is pivotal in controlling and shaping adolescent behaviors, and it undergoes heightened plasticity during that time, such that interference with dopamine signaling can have long-lasting behavioral consequences. Here we sought to gain mechanistic insight into this dopamine-sensitive period and its impact on behavior. In mice, dopamine transporter (DAT) blockade from postnatal (P) day 22 to 41 increases aggression and sensitivity to amphetamine (AMPH) behavioral stimulation in adulthood. Here, we refined this sensitive window to P32-41 and identified increased firing of dopaminergic neurons in vitro and in vivo as a neural correlate to altered adult behavior. Aggression can result from enhanced impulsivity and cognitive dysfunction, and dopamine regulates working memory and motivated behavior. Hence, we assessed these behavioral domains and found that P32-41 DAT blockade increases impulsivity but has no effect on cognition, working memory, or motivation in adulthood. Lastly, using optogenetics to drive dopamine neurons, we find that increased VTA but not SNc dopaminergic activity mimics the increase in impulsive behavior in the Go/NoGo task observed after adolescent DAT blockade. Together our data provide insight into the developmental origins of aggression and impulsivity that may ultimately improve diagnosis, prevention, and treatment strategies for related neuropsychiatric disorders.

Rehabilitation of Children and Adolescents with Deviant Behavior and Neurosis-Like Pseudoneurasthenic States of Residual Organic Genesis

The article presents the content and modes of treatment and rehabilitation of children and adolescents with related neuropsychiatric disorders accompanied by behavioral abnormalities. The complexity and ambiguity of solving this problem by many researchers, as well as the tendency to deepen the understanding of the content, means and methods of rehabilitation of children and adolescents in various directions related to school and social and labor maladjustment, risk factors for various forms of behavioral disorders, were noted. The general trend is to develop and carry out for this contingent of sick children and adolescents not only effective drug therapy, but also special measures for their sufficient social adaptation in the future. On the basis of methodological and organizational principles, which include partnership, comprehensiveness of influence, the unity of psychosocial and biological methods of influence, the sequence of rehabilitation measures, the implementation of a systemic approach to the rehabilitation of children and adolescents with deviant behavior and neurotic-like pseudoneurasthenic states of residual organic genesis is revealed. On the basis of the results of the examination and the identification of the causes of the formation of behavioral disorders of 576 children and adolescents aged 7 to 17 years, developed and tested medically differentiated rehabilitation regimens are given, the effectiveness of which is confirmed by the final examinations and the 1-3-year catamnesis of 438 children and adolescents or 76.0 % of the total number who received a full course of restorative therapy and correction of behavioral disorders. It was concluded that the results of restorative therapy and correction of behavioral disorders of children and adolescents with deviant behavior and neurotic-like pseudoneurasthenic states of residual organic genesis require further stabilization of positive premorbid traits in family relationships. In this regard, it is important to further correct the communication difficulties of adolescents in social and psychological training for the formation of self-regulation skills in establishing and maintaining positive relationships with peers and significant adults.

Clinical genetics of schizophrenia and related neuropsychiatric disorders

Rare structural variants have turned out to be the long sought for genetic variants of (relatively) high effect size for schizophrenia. Delineating the 22q11.2 microdeletion as the first molecular subtype of schizophrenia was a milestone in schizophrenia research, foreshadowing a more general role for rare copy number variation (CNV) in schizophrenia. The 22q11.2 microdeletion has a high effect size – one in every four individuals born with this deletion develops schizophrenia – and a relatively high prevalence for a rare condition. Discovery of this human genetic high-risk model for schizophrenia has shown how genetics can change clinical management, and also provide new opportunities for animal and cellular models. Further new findings indicate a role for tandem repeat expansion, other less complex rare variants, and collective background effects of common variants in the genetics of schizophrenia. Thus, the genetic architecture of schizophrenia is taking shape, with further advances on the horizon.

Did King Yeongjo (1694–1776) of Joseon Dynasty Korea suffer dementia during the last decade of his reign?

ABSTRACT King Yeongjo, the 21st king of Joseon (18th Century Korea), reigned during the prime years of the dynasty and was its oldest king. Despite his many accomplishments, debate surrounds his reputed display of the symptoms of dementia during the last years of his life. The King showed signs of dementia after 40 years of his regency in 1762 at the age of 69 years, including disorientation, cognitive impairment, amnestic disorder and so on. We examined evidence from the Annals of the Joseon Dynasty and related research papers. Additionally, dementia specialists were asked to undertake a survey to provide objectivity to the literary findings. Prior to his death in 1776, 25 meaningful dementia symptoms were recorded in the Annals across a 10-year period. However, despite indications of dementia, the Joseon dynasty supported him as a king and helped him retain his dignity until the end. This suggests that historical perception changes regarding dementia may also inform current-day attitudes to improve the living standards of patients suffering from dementia and related neuropsychiatric disorders.

Immunological Dysfunction in Tourette Syndrome and Related Disorders.

Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the disinhibition of the corticostriatal–thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive–compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome.

Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is comprised of several conditions characterized by alterations in social interaction, communication, and repetitive behaviors. Genetic and environmental factors contribute to the heterogeneous development of ASD behaviors. Several rodent models display ASD-like phenotypes, including repetitive behaviors. In this review article, we discuss the potential neural mechanisms involved in repetitive behaviors in rodent models of ASD and related neuropsychiatric disorders. We review signaling pathways, neural circuits, and anatomical alterations in rodent models that display robust stereotypic behaviors. Understanding the mechanisms and circuit alterations underlying repetitive behaviors in rodent models of ASD will inform translational research and provide useful insight into therapeutic strategies for the treatment of repetitive behaviors in ASD and other neuropsychiatric disorders.

What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?

Objective: The goal of this article is to review the past decade's literature and provide a critical commentary on the involvement of immunological mechanisms in normal brain development, as well as its role in the pathophysiology of Tourette syndrome, other Chronic tic disorders (CTD), and related neuropsychiatric disorders including Obsessive-compulsive disorder (OCD) and Attention deficit hyperactivity disorder (ADHD).Methods: We conducted a literature search using the Medline/PubMed and EMBASE electronic databases to locate relevant articles and abstracts published between 2009 and 2020, using a comprehensive list of search terms related to immune mechanisms and the diseases of interest, including both clinical and animal model studies.Results: The cellular and molecular processes that constitute our “immune system” are crucial to normal brain development and the formation and maintenance of neural circuits. It is also increasingly evident that innate and adaptive systemic immune pathways, as well as neuroinflammatory mechanisms, play an important role in the pathobiology of at least a subset of individuals with Tourette syndrome and related neuropsychiatric disorders In the conceptual framework of the holobiont theory, emerging evidence points also to the importance of the “microbiota-gut-brain axis” in the pathobiology of these neurodevelopmental disorders.Conclusions: Neural development is an enormously complex and dynamic process. Immunological pathways are implicated in several early neurodevelopmental processes including the formation and refinement of neural circuits. Hyper-reactivity of systemic immune pathways and neuroinflammation may contribute to the natural fluctuations of the core behavioral features of CTD, OCD, and ADHD. There is still limited knowledge of the efficacy of direct and indirect (i.e., through environmental modifications) immune-modulatory interventions in the treatment of these disorders. Future research also needs to focus on the key molecular pathways through which dysbiosis of different tissue microbiota influence neuroimmune interactions in these disorders, and how microbiota modification could modify their natural history. It is also possible that valid biomarkers will emerge that will guide a more personalized approach to the treatment of these disorders.

Juvenile high–fat diet–induced senescent glial cells in the medial prefrontal cortex drives neuropsychiatric behavioral abnormalities in mice

The prefrontal cortex (PFC) plays an important role in regulating anxiety–like phenotypes and social behaviors, and impairments in this brain region has been linked to social deficits in mammals. Childhood obesity is associated with an increased risk of neuropsychiatric behavioral abnormalities, including attenuated social preference and increased anxiety–like behaviors in adulthood. However, little data are available on the impact of obesity during adolescence on PFC–dependent behaviors. Herein, we use the mice pups to illuminate whether and how high–fat diet (HFD) feeding in adolescence affects medial prefrontal cortex (mPFC)–dependent behaviors, and what the underlying cellular and molecular mechanism is. We found that juvenile HFD feeding results in the accumulation of senescent astrocytes and microglia in the mPFC of mice. Furthermore, we found a causal link between the accumulation of senescent glial cells and HFD–induced neuropsychiatric behavioral abnormalities. Pharmacological clearance of senescent glial cells in HFD–fed mice enhances neuronal activity and reserves synaptic excitatory/inhibitory balance, thus preserving normal behaviors. Collectively, these results show that senescent glial cells play a significant role in the initiation and progression of juvenile obesity–mediated neuropsychiatric behavioral abnormalities, and suggest that targeting senescent glial cells may provide a therapeutic avenue for the treatment of obesity–related neuropsychiatric disorders in children.

Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion

The effective treatment of bipolar disorder (BD) represents a significant unmet medical need. Although lithium remains a mainstay of treatment for BD, limited knowledge regarding how it modulates affective behavior has proven an obstacle to discovering more effective mood stabilizers with fewer adverse side effects. One potential mechanism of action of lithium is through inhibition of the serine/threonine protein kinase GSK3β, however, relevant substrates whose change in phosphorylation may mediate downstream changes in neuroplasticity remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived neuronal cells and stable isotope labeling by amino acids in cell culture (SILAC) along with quantitative mass spectrometry to identify global changes in the phosphoproteome upon inhibition of GSK3α/β with the highly selective, ATP-competitive inhibitor CHIR-99021. Comparison of phosphorylation changes to those induced by therapeutically relevant doses of lithium treatment led to the identification of collapsin response mediator protein 2 (CRMP2) as being highly sensitive to both treatments as well as an extended panel of structurally distinct GSK3α/β inhibitors. On this basis, a high-content image-based assay in hiPSC-derived neurons was developed to screen diverse compounds, including FDA-approved drugs, for their ability to mimic lithium’s suppression of CRMP2 phosphorylation without directly inhibiting GSK3β kinase activity. Systemic administration of a subset of these CRMP2-phosphorylation suppressors were found to mimic lithium’s attenuation of amphetamine-induced hyperlocomotion in mice. Taken together, these studies not only provide insights into the neural substrates regulated by lithium, but also provide novel human neuronal assays for supporting the development of mechanism-based therapeutics for BD and related neuropsychiatric disorders.

P.219 Brief exposure to high fat diet impairs the prefrontal plasticity in juvenile and adult animals: role of glucocorticoids

The prefrontal cortex (PFC) plays an important role in regulating anxiety–like phenotypes and social behaviors, and impairments in this brain region has been linked to social deficits in mammals. Childhood obesity is associated with an increased risk of neuropsychiatric behavioral abnormalities, including attenuated social preference and increased anxiety–like behaviors in adulthood. However, little data are available on the impact of obesity during adolescence on PFC–dependent behaviors. Herein, we use the mice pups to illuminate whether and how high–fat diet (HFD) feeding in adolescence affects medial prefrontal cortex (mPFC)–dependent behaviors, and what the underlying cellular and molecular mechanism is. We found that juvenile HFD feeding results in the accumulation of senescent astrocytes and microglia in the mPFC of mice. Furthermore, we found a causal link between the accumulation of senescent glial cells and HFD–induced neuropsychiatric behavioral abnormalities. Pharmacological clearance of senescent glial cells in HFD–fed mice enhances neuronal activity and reserves synaptic excitatory/inhibitory balance, thus preserving normal behaviors. Collectively, these results show that senescent glial cells play a significant role in the initiation and progression of juvenile obesity–mediated neuropsychiatric behavioral abnormalities, and suggest that targeting senescent glial cells may provide a therapeutic avenue for the treatment of obesity–related neuropsychiatric disorders in children.

Pathogenetical and Neurophysiological Features of Patients with Autism Spectrum Disorder: Phenomena and Diagnoses.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is accompanied by social deficits, repetitive and restricted interests, and altered brain development. The majority of ASD patients suffer not only from ASD itself but also from its neuropsychiatric comorbidities. Alterations in brain structure, synaptic development, and misregulation of neuroinflammation are considered risk factors for ASD and neuropsychiatric comorbidities. Electroencephalography has been developed to quantitatively explore effects of these neuronal changes of the brain in ASD. The pineal neurohormone melatonin is able to contribute to neural development. Also, this hormone has an inflammation-regulatory role and acts as a circadian key regulator to normalize sleep. These functions of melatonin may play crucial roles in the alleviation of ASD and its neuropsychiatric comorbidities. In this context, this article focuses on the presumable role of melatonin and suggests that this hormone could be a therapeutic agent for ASD and its related neuropsychiatric disorders.

Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats.

Background and PurposeDepression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin‐3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug‐like properties. We proposed that a hydrocarbon‐stapled mimetic of relaxin‐3, when administered intranasally, might be uniquely applicable to the treatment of these disorders.Experimental ApproachWe designed a series of hydrocarbon‐stapled relaxin‐3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin‐3 and the lead stapled mimetic in rat models of anxiety and depression.Key ResultsWe developed an i,i+7 stapled relaxin‐3 mimetic that manifested a stabilized α‐helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin‐3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant‐like activity in anxiety‐ and depression‐related behaviour paradigms.Conclusions and ImplicationsOur preclinical findings demonstrate that targeting the relaxin‐3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin‐3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

Interneuron Transplantation Creates New Network States and Rescues Social Behavior Deficits in a Mouse Model of Autism

Abstract INTRODUCTION Inhibitory interneuron transplantation is a prospective treatment for neuropsychiatric disorders, but it is unclear whether transplantation might elicit therapeutic effects by reversing preexisting abnormalities, nonspecifically increasing synaptic inhibition, or engaging mechanisms that vary depending on recipient background and behavioral state. METHODS We transplanted wild-type embryonic interneuron precursors into mice lacking an autism-associated gene, Pten, in inhibitory interneurons. Additionally, we performed transplantation into wild-type recipient mice, and then examined the recipient behavior, cellular physiology in Vitro, and network physiology in Vivo. RESULTS Transplantation rescued social behavior deficits in Pten mutants without normalizing excessive synaptic inhibition in Vitro or reduced baseline gamma oscillatory power in Vivo. However, transplantation altered recipient electroencephalography (EEG) responses observed specifically during periods of social interaction. When transplantation was performed into wild-type recipients, the subtype composition of the transplanted population varied from that observed in Pten mutants, and, moreover, recipients did not exhibit alterations to social behavior or related EEG responses. CONCLUSION Interneuron transplantation elicits recipient- and behavioral state-dependent effects, and normalizes behavior by creating new patterns of network activity, rather than restoring wild-type states. Interneuron transplantation may provide a novel therapeutic approach to the treatment of autism and related neuropsychiatric disorders.

Effects of Oxytocin Administration on Oxidative Markers in the Temporal Lobe of Aged Rats

Considering the relevance of oxidative stress in aging and antioxidant properties of oxytocin, which we previously demonstrated, we studied the effects of intraperitoneal oxytocin administration (10 mg/kg body mass for 12 days) on enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), and also on malonic dialdehyde (MDA) level in the brain temporal lobe of aged (2-year-old) Wistar rats. In these rats, oxytocin treatment provided a significantly lower SOD enzymatic activity, somewhat greater GPx activity, and significantly lower MDA concentration, when compared to the respective indices in aged control rats. It is concluded that, due to its antioxidant effect, oxytocin can be considered a candidate for the development of a new therapeutic modality in aging and in related neuropsychiatric disorders.

Genetic influences on cortical myelination in the human brain.

Cortical myelination, which is essential for interneuronal communication and neurodevelopment, has been reported to be under genetic control. However, the degree to which genes contribute to the variability of myelination, the pattern of genetic control, and how genes influence the organization of myelination are largely unknown. To answer these questions, the present study calculated heritability estimates for myelination of the cortical regions using the high quality structural magnetic resonance imaging (MRI) scans from the Human Connectome Project pedigree cohort (n = 873, 383/490 M/F, 22-36 years of age). Then, we used transcriptional profiles to evaluate the contribution of myelination-related genes (data from the Allen Human Brain Atlas) to explain interregional variations in cortical myelination. Our results showed that all the cortical areas were modestly to moderately influenced by genetic factors (h2 = 29%-66%, all Ps < 0.05 after Bonferroni correction). The genetic control of cortical myelination showed bilateral symmetry and an anterior-to-posterior gradation. A bivariate model indicated that the regions are strongly genetically correlated with their homologs in the opposite cerebral hemisphere. A cross-modal analysis did not find a correlation between cortical myelination and the expression levels of myelination-related genes. This could have been due to the small number of samples with expression data in each cortical region. Overall, our findings suggest that cortical myelination is shaped by genetic factors and may be useful to bridge the underlying genetic variants and the cognitive functioning and related neuropsychiatric disorders.

Reverse translated and gold standard continuous performance tests predict global cognitive performance in schizophrenia

Attentional dysfunction contributes to functional impairments in schizophrenia (SZ). Sustained attention is typically assessed via continuous performance tasks (CPTs), though many CPTs have limited cross-species translational validity and place demands on additional cognitive domains. A reverse-translated 5-Choice Continuous Performance Task (5C-CPT) for human testing—originally developed for use in rodents—was designed to minimize demands on perceptual, visual learning, processing speed, or working memory functions. To-date, no studies have validated the 5C-CPT against gold standard attentional measures nor evaluated how 5C-CPT scores relate to cognition in SZ. Here we examined the relationship between the 5C-CPT and the CPT-Identical Pairs (CPT-IP), an established and psychometrically robust measure of vigilance from the MATRICS Consensus Cognitive Battery (MCCB) in a sample of SZ patients (n = 35). Relationships to global and individual subdomains of cognition were also assessed. 5C-CPT and CPT-IP measures of performance (d-prime) were strongly correlated (r = 0.60). In a regression model, the 5C-CPT and CPT-IP collectively accounted for 54% of the total variance in MCCB total scores, and 27.6% of overall cognitive variance was shared between the 5C-CPT and CPT-IP. These results indicate that the reverse translated 5C-CPT and the gold standard CPT-IP index a common attentional construct that also significantly overlaps with variance in general cognitive performance. The use of simple, cross-species validated behavioral indices of attentional/cognitive functioning such as the 5C-CPT could accelerate the development of novel generalized pro-cognitive therapeutics for SZ and related neuropsychiatric disorders.

Behavioral and Neurochemical Phenotyping of Mice Incapable of Homer1a Induction

Immediate early and constitutively expressed products of the Homer1 gene regulate the functional assembly of post-synaptic density proteins at glutamatergic synapses to influence excitatory neurotransmission and synaptic plasticity. Earlier studies of Homer1 gene knock-out (KO) mice indicated active, but distinct, roles for IEG and constitutively expressed Homer1 gene products in regulating cognitive, emotional, motivational and sensorimotor processing, as well as behavioral and neurochemical sensitivity to cocaine. More recent characterization of transgenic mice engineered to prevent generation of the IEG form (a.k.a Homer1a KO) pose a critical role for Homer1a in cocaine-induced behavioral and neurochemical sensitization of relevance to drug addiction and related neuropsychiatric disorders. Here, we extend our characterization of the Homer1a KO mouse and report a modest pro-depressant phenotype, but no deleterious effects of the KO upon spatial learning/memory, prepulse inhibition, or cocaine-induced place-conditioning. As we reported previously, Homer1a KO mice did not develop cocaine-induced behavioral or neurochemical sensitization within the nucleus accumbens; however, virus-mediated Homer1a over-expression within the nucleus accumbens reversed the sensitization phenotype of KO mice. We also report several neurochemical abnormalities within the nucleus accumbens of Homer1a KO mice that include: elevated basal dopamine and reduced basal glutamate content, Group1 mGluR agonist-induced glutamate release and high K+-stimulated release of dopamine and glutamate within this region. Many of the neurochemical anomalies exhibited by Homer1a KO mice are recapitulated upon deletion of the entire Homer1 gene; however, Homer1 deletion did not affect NAC dopamine or alter K+-stimulated neurotransmitter release within this region. These data show that the selective deletion of Homer1a produces a behavioral and neurochemical phenotype that is distinguishable from that produced by deletion of the entire Homer1 gene. Moreover, the data indicate a specific role for Homer1a in regulating cocaine-induced behavioral and neurochemical sensitization of potential relevance to the psychotogenic properties of this drug.

Meta-analyses of RELN variants in neuropsychiatric disorders.

Reelin is a critical extracellular matrix glycoprotein and implicated in neurodevelopment and psychiatric disorders in animal model studies. The genetic polymorphism of RELN has also been reported to be associated with several psychiatric disorders, but the results remain controversial. Here, we conducted meta-analyses of RELN gene SNPs and related neuropsychiatric disorders (schizophrenia, autistic spectrum disorders, attention-deficit hyperactivity disorder, Alzheimer's disease and bipolar disorders). A total of 12 SNPs (rs736707, rs362691, rs607755, rs2229864, rs7341475, rs262355, rs362719, rs11496125, g.-888G>C, rs2299356, rs528528, and rs4298437) in RELN gene were included into meta-analyses. Subgroup analyses based on ethnicity were performed. We found that RELN rs736707 was significantly related with psychiatric disorders (schizophrenia, autism spectrum disorders and attention-deficit hyperactivity disorder) in Asian group (C vs T, OR=1.26, 95% CI=1.13-1.41, P<0.01, FDR<0.01), and rs7341475 was only significantly associated with reduced risk of schizophrenia in Caucasian (A vs G, OR=0.88, 95% CI=0.82-0.95, P<0.01, FDR<0.01). No association of other SNPs and psychiatric disorders is found. These findings suggest a role of RELN SNPs in psychiatric diseases, and indicate that further researches in populations with different genetic background and studies with larger sample size are of great value.