nNOS-mediated protein-protein interactions:promising targets for treating neurological and neuropsychiatric disorders

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.Nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS)in the brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.

From Signals to Solutions: Exploring Early Detection of Neuropsychiatric and Neurodevelopment Disorders through Biomarkers

In 2013, the percentage of children ranging from 5 to 17 years who reported being diagnosed with autism surged to 1.2% from 0.1% in 1997 [1]. Alongside this increase in the incidence of autism in children, there were findings of a 21% increase in children who displayed behavioral and conduct problems from 2019 to 2020 [2]. Early detection of neuropsychiatric and neurodevelopmental disorders in children is critical for timely intervention and improved long-term outcomes. With early intervention, there is better aptitude to support healthy development and give proper treatment to attain a better quality of life. This paper explores studies aimed at enhancing the early detection of these disorders through the use of biomarkers with the aim of creating a bridge between the worlds of research and clinical practice. The disorders in this paper specifically discussed are Major Depressive Disorder, Bipolar Disorder, and Autism Spectrum Disorder. With this bridge, we can foster collaborations and encourage further advancement in the field of early detection and intervention.

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

In the central nervous system,nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS).In the past 20 years,the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders.In particular,the interactions between the PDZ domain of nNOS and its adaptor proteins,including post-synaptic density 95,the carboxy-terminal PDZ ligand of nNOS,and the serotonin transporter,significantly influence the subcellular localization and functions of nNOS in the brain.The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders.Here,we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.

Human stem cell modeling of neuropsychiatric disorders:from polygenicity to convergence

Neuropsychiatric disorders(NPD)are prevalent and devastating,posing an enormous socioeconomic burden to modern society.Recent genetic studies of NPD have identified a plethora of common genetic risk variants with small effect sizes and rare risk variants of high penetrance.While exciting,there is a pressing need to translate these genetic discoveries into better understanding of disease biology and more tailored clinical interventions.Human induced pluripotent stem cell(hiPSC)-derived 2D and 3D neural cultures are becoming a promising cellular model for bridging the gap between genetic findings and disease biology for NPD.Leveraging the accessibility of patient biospecimen to convert into stem cells and the power of genome editing technology to engineer disease risk variants,hiPSC model holds the promise to disentangle the disease polygenicity,model genetic interaction with environmental factors,and uncover convergent gene pathways that may be targeted for more tailored clinical intervention.

Management of post-stroke neuropsychiatric disorders

Post-stroke neuropsychiatric(NP) disorders are common and have complex etiologies.Multiple factors such as lesion location, personality characteristics, socioeconomic status, pre-stroke psychiatric history, and family support are the determining factors in most cases. Although depression and anxiety are more common, emotional incontinence and catastrophic reactions are also frequently observed. Post-stroke depression(PSD)has been associated with an increased risk of stroke recurrence. Despite its serious consequences and high prevalence, PSD remains undetected and untreated. Treatment options of NP disorders depend on severity, presentation at the time of diagnosis, and patient cooperation, and include antidepressants, mood stabilizers, exercise therapy, psychotherapy, and even revascularization. The efficient management of NP disorders improves outcomes, quality of life, and survival rates in post-stroke patients. However,very few studies have identified definitive treatment for these patients; therefore, further research is required.

Postzygotic mosaic mutations in autism spectrum disorder and other neuropsychiatric disorders

Autism,or autism spectrum disorder(ASD),refers to a range of neurodevelopmental disorders characterized by:(1)impaired social interaction,(2)impaired verbal and non-verbal communication,and(3)restricted and repetitive behavior[1].Although typically not diagnosed until the age of 3,symptoms can present during infancy.Early intervention with behavioral therapies has been shown to improve learning,communication,and social skills.

Neuropsychiatric issues after stroke: Clinical significance and therapeutic implications

A spectrum of neuropsychiatric disorders is a common complication from stroke.Neuropsychiatric disorders after stroke have negative effects on functional recovery,increasing the rate of mortality and disability of stroke survivors.Given the vital significance of maintaining physical and mental health in stroke patients,neuropsychiatric issues after stroke have raised concerns by clinicians and researchers.This mini-review focuses on the most common non-cognitive functional neuropsychiatric disorders seen after stroke,including depressive disorders,anxiety disorders,post-traumatic stress disorder,psychosis,and psychotic disorders.For each condition,the clinical performance,epidemiology,identification of the therapeutic implication,and strategies are reviewed and discussed;the main opinions and perspectives presented here are based on the latest controlled studies,meta-analysis,or updated systematic reviews.In the absence of data from controlled studies,consensus recommendations were provided accordingly.

Does COVID-19 increase the risk of neuropsychiatric sequelae? Evidence from a mendelian randomization approach

Observational studies based on electronic health records (EHR) report anincreased risk of neurological/neuropsychiatric sequelae for patients who havehad coronavirus disease 2019 (COVID-19). However, these studies may sufferfrom biases such as unmeasured confounding, residual reverse causality, or lackof precision in EHR-based diagnoses. To rule out these biases, we tested causallinks between COVID-19 and different potential neurological/neuropsychiatricsequelae through a two-sample Mendelian randomization analysis of summarystatistics from large Genome-Wide Association Scans of susceptibility to COVID-19 and different neurological and neuropsychiatric disorders, including majordepression, anxiety, schizophrenia, stroke, Parkinson’s and Alzheimer’s diseases.We found robust evidence suggesting that COVID-19 – notably the hospitalizedand most severe forms – carries an increased risk of neuropsychiatric sequelae,particularly Alzheimer’s disease, and to a lesser extent anxiety disorder. In linewith a large longitudinal EHR-based study, this evidence was stronger for moresevere COVID-19 forms. These results call for a targeted screening strategy totackle the post-COVID neuropsychiatric pandemic.

Quality of Life with Flotation Therapy for a Person Diagnosed with Attention Deficit Disorder,Atypical Autism,PTSD,Anxiety and Depression

The aim of this single-subject study was to report experiences from one and a half years of regular floating as described by a person with neuropsychiatric and mental health disorders. Floating, or Flotation Restricted Environmental Stimulation Technique, involves relaxation and sensory deprivation by means of resting in a tank with highly salted and body-tempered water. The subject, a 24-year-old woman diagnosed with attention deficit hyperactivity disorder, atypical autism, post-traumatic stress disorder, anxiety and depression floated regularly for one and a half years. Interviews regarding her experiences were analyzed and the main findings involved a subjective sense of improved quality of life, wellbeing and healthy behavior. There were no negative effects from treatment. Results suggest that floating may have beneficial therapeutic effects on mental health. Further studies that evaluate the efficacy and possible effects of floating with regard to mental health are needed.

Brain-derived neurotrophic factor rs6265(Val66Met)single nucleotide polymorphism as a master modifier of human pathophysiology

Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family.Since its discovery in 1978,this enigmatic molecule has spawned more than 27,000 publications,most of which are focused on neurological disorders.Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems.It is becoming increasingly clear,however,that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement.Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology.To that point,we recently found that a common nonsynonymous(Val66→Met)single nucleotide polymorphism in the brain-derived neurotrophic factor gene(rs6265)not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females.In addition to a short description of recent results from associative neuropsychiatric studies,this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.

Synaptic development of layer V pyramidal neurons in the prenatal human prefrontal neocortex: a Neurolucida-aided Golgi study

The prefrontal neocortex is involved in many high cognitive functions in humans.Deficits in neuronal and neurocircuitry development in this part of the cerebrum have been associated with various neuropsychiatric disorders in adolescents and adults.There are currently little available data regarding prenatal dendrite and spine formation on projecting neurons in the human prefrontal neocortex.Previous studies have demonstrated that Golgi silver staining can identify neurons in the frontal lobe and visual cortex in human embryos.In the present study,five fetal brains,at 19,20,26,35,and 38 gestational weeks,were obtained via the body donation program at Xiangya School of Medicine,Central South University,China.Golgi-stained pyramidal neurons in layer V of Brodmann area 46 in fetuses were quantitatively analyzed using the Neurolucida morphometry system.Results revealed that somal size,total dendritic length,and branching points of these neurons increased from 26 to 38 gestational weeks.There was also a large increase in dendritic spines from 35 to 38 gestational weeks.These findings indicate that,in the human prefrontal neocortex,dendritic growth in layer V pyramidal neurons occurs rapidly during the third trimester of gestation.The use of human fetal brain tissue was approved by the Animal Ethics Committee of Xiangya School of Medicine,Central South University,China(approval No.2011-045)on April 5,2011.

The Relative Deficiency of Potassium Ions in Nerve Cells Causes Abnormal Functions and Neurological and Mental Diseases

The difference of intracellular potassium (K+) and extracellular sodium (Na+) concentrations in nerve cells plays an important role in the functional activities of the nervous system. The maintenance of this difference mainly depends on the number and efficiency of Na, K-ATPase. However, due to the functional activity of nerve cells, this system often loses its balance. An undetectable phenomenon is the relative deficiency of potassium in nerve cells in specific brain regions or neural network structures, which leads to dysfunction of specific nerve cell populations or brain regions, thus leading to different types of neurological disorders or diseases. The relative deficiency of potassium ions in nerve cells may be caused by the competitive failure of nerve cells to effectively use potassium ions stored in the body, and the core reason may be related to insufficient potassium obtained through diet or effectively absorbed by the digestive system. Therefore, a simple strategy is to treat a patient by taking appropriate potassium orally. This paper presents a case with great success by using such a method to treat a patient with major depression.

Group A streptococcal antigen exposed rat model to investigate neurobehavioral and cardiac complications associated with post-streptococcal autoimmune sequelae

Background:The neuropsychiatric disorders due to post-streptococcal autoimmune complications such as Sydenham's chorea(SC)are associated with acute rheumatic fever and rheumatic heart disease(ARF/RHD).An animal model that exhibits char-acteristics of both cardiac and neurobehavioral defects in ARF/RHD would be an important adjunct for future studies.Since age,gender,strain differences,and geno-types impact on the development of autoimmunity,we investigated the behavior of male and female Wistar and Lewis rat strains in two age cohorts(6 weeks and 12 weeks)under normal husbandry conditions and following exposure to group A streptococcus(GAS).Methods:Standard behavioral assessments were performed to determine the impair-ments in fine motor control(food manipulation test),gait and balance(beam walk-ing test),and obsessive-compulsive behavior(grooming and marble burying tests).Furthermore,electrocardiography,histology,and behavioral assessments were per-formed on male and female Lewis rats injected with GAS antigens.Results:For control Lewis rats there were no significant age and gender dependent differences in marble burying,food manipulation,beam walking and grooming be-haviors.In contrast significant age-dependent differences were observed in Wistar rats in all the behavioral tests except for food manipulation.Therefore,Lewis rats were selected for further experiments to determine the effect of GAS.After ex-posure to GAS,Lewis rats demonstrated neurobehavioral abnormalities and cardiac pathology akin to SC and ARF/RHD,respectively.Conclusion:We have characterised a new model that provides longitudinal stability of age-dependent behavior,to simultaneously investigate both neurobehavioral and cardiac abnormalities associated with post-streptococcal complications.

众脑之力:通过开放神经影像数据和大规模协作催化神经精神疾病的创新发现

Recent advances in open neuroimaging data are enhancing our comprehension of neuropsychiatric disorders.By pooling images from various cohorts,statistical power has increased,enabling the detection of subtle abnormalities and robust associations,and fostering new research methods.Global collaborations in imaging have furthered our knowledge of the neurobiological foundations of brain disorders and aided in imaging-based prediction for more targeted treatment.Large-scale magnetic resonance imaging initiatives are driving innovation in analytics and supporting generalizable psychiatric studies.We also emphasize the significant role of big data in understanding neural mechanisms and in the early identification and precise treatment of neuropsychiatric disorders.However,challenges such as data harmonization across different sites,privacy protection,and effective data sharing must be addressed.With proper governance and open science practices,we conclude with a projection of how large-scale imaging resources and collaborations could revolutionize diagnosis,treatment selection,and outcome prediction,contributing to optimal brain health.

Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders

The P2X4 receptor(P2X4)is an ATP-gated cation channel that is highly permeable to Ca2+and widely expressed in neuronal and glial cell types throughout the central nervous system(CNS).A growing body of evidence indicates that P2X4 plays key roles in numerous central disorders.P2X4 trafficking is highly regulated and consequently in normal situations,P2X4 is present on the plasma membrane at low density and found mostly within intracellular endosomal/lysosomal compartments.An increase in the de novo expression and/or surface density of P2X4 has been observed in microglia and/or neurons during pathological states.This review aims to summarize knowledge on P2X4 functions in CNS disorders and provide some insights into the relative contributions of neuronal and glial P2X4 in pathological contexts.However,determination of the cell-specific functions of P2X4 along with its intracellular and cell surface roles remain to be elucidated before its potential as a therapeutic target in multiple disorders can be defined.

PsyMuKB: An Integrative De Novo Variant Knowledge Base for Developmental Disorders

De novo variants(DNVs)are one of the most significant contributors to severe earlyonset genetic disorders such as autism spectrum disorder,intellectual disability,and other developmental and neuropsychiatric(DNP)disorders.Presently,a plethora of DNVs have been identified using next-generation sequencing,and many efforts have been made to understand their impact at the gene level.However,there has been little exploration of the effects at the isoform level.The brain contains a high level of alternative splicing and regulation,and exhibits a more divergent splicing program than other tissues.Therefore,it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders.To facilitate a better usage and improve the isoform-level interpretation of variants,we developed NeuroPsychiatric Mutation Knowledge Base(PsyMuKB).It contains a comprehensive,carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoformspecific mutations.PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations,such as expression,transcript genomic structures,protein interactions,and the mutation sites mapped on the protein structures.It also provides an easy-to-use web interface,allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms.PsyMuKB thus constitutes a valuable resource for identifying tissue-specific DNVs for further functional studies of related disorders.PsyMuKB is freely accessible at http://psymukb.net.

Brain Banks Spur New Frontiers in Neuropsychiatric Research and Strategies for Analysis and Validation

Neuropsychiatric disorders affect hundreds of millions of patients and families worldwide.To decode the molecular framework of these diseases,many studies use human postmortem brain samples.These studies reveal brain-specific genetic and epigenetic patterns via highthroughput sequencing technologies.Identifying best practices for the collection of postmortem brain samples,analyzing such large amounts of sequencing data,and interpreting these results are critical to advance neuropsychiatry.We provide an overview of human brain banks worldwide,including progress in China,highlighting some well-known projects using human postmortem brain samples to understand molecular regulation in both normal brains and those with neuropsychiatric disorders.Finally,we discuss future research strategies,as well as state-of-the-art statistical and experimental methods that are drawn upon brain bank resources to improve our understanding of the agents of neuropsychiatric disorders.