Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Progress on the roles of MEF2C in neuropsychiatric diseases

Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.

New Horizons for Phenotyping Behavior in Rodents: The Example of Depressive-Like Behavior

The evolution of the field of behavioral neuroscience is significantly dependent on innovative disruption triggered by our ability to model and phenotype animal models of neuropsychiatric disorders. The ability to adequately elicit and measure behavioral parameters are the fundaments on which the behavioral neuroscience community establishes the pathophysiological mechanisms of neuropsychiatric disorders as well as contributes to the development of treatment strategies for those conditions. Herein, we review how mood disorders, in particular depression, are currently modeled in rodents, focusing on the limitations of these models and particularly on the analyses of the data obtained with different behavioral tests. Finally, we propose the use of new paradigms to study behavior using multidimensional strategies that better encompasses the complexity of psychiatric conditions, namely depression; these paradigms provide holistic phenotyping that is applicable to other conditions, thus promoting the emergence of novel findings that will leverage this field.

Neuropsychiatric Disorders and Frailty in Older Adults over the Spectrum of Cancer: A Narrative Review

Background: The interplay between different neuropsychiatric conditions, beyond dementia, in the presence of a diagnosis of cancer in older adults may mediate patients’ fitness and cancer-related outcomes. Here, we aimed to investigate the presence of depression, sleep disturbances, anxiety, attitude, motivation, and support in older adults receiving a diagnosis of cancer and the dimension of frailty in order to understand the magnitude of the problem. Methods: This review provides an update of the state of the art based on references from searches of PubMed between 2000 and June 2021. Results: The evidence obtained underscored the tight association between frailty and unfavorable clinical outcomes in older adults with cancer. Given the intrinsic correlation of neuropsychiatric disorders with frailty in the realm of cancer survivorship, the evidence showed they might have a correlation with unfavorable clinical outcomes, late-life geriatric syndromes and higher degree of frailty. Conclusions: The identification of common vulnerabilities among neuropsychiatric disorders, frailty, and cancer may hold promise to unmask similar shared pathways, potentially intercepting targeted new interventions over the spectrum of cancer with the delivery of better pathways of care for older adults with cancer.

Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Aim: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders. Background: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders. Objectives: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database. Methods: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound. Results: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone. Conclusion: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

Connectional architecture of the prefrontal cortex in the marmoset brain

The primate prefrontal cortex (PFC) has greatly expanded to evolve specialized architecture, but its roles in top-down brain control remain enigmatic. Based on connectomics mapping of the marmoset PFC, we characterized two contrasting features of corticocortical and corticostriatal projections. One is the "focalness" of projections, exemplified by multiple columnar axonal terminations in the cortical layers and the other is the "widespreadness" of weaker projections, whose patterns consisted of several common motifs representing the framework of PFC connectivity. We clarified the topographic rules of distribution for these features, which should constrain how PFC neurons can coordinate to control the target regions as populations. These features are observed only primitively in rodents and are considered critical in understanding the roles of the PFC in neuropsychiatric disorders.

Treatment of noncognitive neuropsychiatric disorders in Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, which is caused by cerebral amyloidosis. Noncognitive neuropsychiatric disorders (NСNPDs) include emotional, behavioral disorders, as well as psychotic symptoms. NСNPDs are almost an obligatory manifestation of this disease, accompany cognitive impairment and are detected at all stages of the disease – from preclinical to the severe dementia stage. As an example, we present a case report of a female patient with mild dementia in AD in whom Akatinol memantine administration resulted in the stabilization of a cognitive defect within one year and a decrease in the severity of emotional and behavioral disorders. The article discusses the indications and contraindications for antipsychotic administration in this disease, NСNPDs treatment in AD, which includes nonpharmacological and pharmacological methods. Accurate analysis of NСNPDs allows to predict the disease course, optimize the treatment, and thereby improve the quality of life of the patient and his relatives and caregivers.