Introduction: Impaired function of brain morphogenic genes is considered one of the predisposing factors for the manifestation of psychiatric and cognitive disorders, such as paranoid schizophrenia (SCZ) and major depressive disorder (MDD). Identification of such genes (genes of neurotrophic factors and guidance molecules among them) and their deleterious genetic variants serves as a key to diagnosis, prevention, and possibly treatment of such disorders. In this study, we have examined the prevalence of genomic variants in brain morphogenic genes in individuals with SCZ and MDD within a Russian population.Methods: We have performed whole-exome sequencing of 21 DNA samples: 11 from individuals with SCZ and 10 with MDD, followed by ARMS (Amplification-Refractory Mutation System) based screening of detected single nucleotide variants (SNVs) in larger groups: 102 for individuals with SCZ, 79 for those with MDD and 103 for healthy donors.Results: Whole-exome sequencing has revealed 226 missense mutations in 79 genes (out of 140 studied), some of which occur in patients with psychiatric disorders significantly more frequently than in healthy donors. We have identified previously undescribed genomic variants in brain morphogenic genes: CDH2 (rs1944294-T and rs17445840-T), DCHS2 (rs11935573-G and rs12500437-G/T) and CDH23 (rs1227051-G/A), significantly associated with the incidence of SCZ and MDD in the Russian population. For some SNVs (rs6265-T, rs1944294-T, rs11935573-G, rs4760-G) sex-biased differences in their prevalence between SCZ/MDD patients and healthy donors was detected.Discussion: However, the functional significance of the SNVs identified has still to be confirmed in cellular and animal models. Once it is fulfilled, these SNVs have the potential to complement the diagnostic toolbox for assessing susceptibility to mental disorders. The data obtained indirectly confirm the importance of adequate brain structure formation for its correct functioning and preservation of mental health.

The etiology and pathogenesis of schizophrenia remain poorly understood, but it has been established that the contribution of heredity to the development of the disease is about 80—85%. Over the past decade, significant progress has been made in the search for specific genetic variants associated with the development of schizophrenia. The review discusses the results of modern large-scale studies aimed at searching for genetic associations with schizophrenia: genome-wide association studies (GWAS) and the search for rare variants (mutations or copy number variations, CNV), including the use of whole exome sequencing. We synthesize data on currently known genes that are significantly associated with schizophrenia and discuss their biological functions in order to identify the main molecular pathways involved in the pathophysiology of schizophrenia.

The increasing prevalence of neurological, neurodegenerative and psychiatric diseases makes it necessary to create appropriate and informative models to study the molecular mechanisms of their pathogenesis and search for promising approaches to treat them. 2D neuron cultures do not display the full complexity of intercellular interactions in the nervous system, and the brains of even primitive mammals are too complex and not always suitable for modeling human brain pathologies. The missing link between 2D-cultures and in vivo models are organotypic 3D-cultures. Such models include surviving brain slices, self-organizing 3D-cultures (neurospheres, brain organoids, assembloids) and brain-on-a-chip cultures. These 3D-models make it possible to reproduce not only the cellular composition of the brain, but to a large extent its architectonics or even to simulate its interactions with other organs and tissues within the body. Their application has already made it possible to obtain data on some molecular mechanisms involved in the development of hereditary, inflammatory and neurodegenerative diseases of the central nervous system, as well as to propose and test some approaches to their treatment. This literature review discusses the possibilities, limitations and the most striking examples of the use of these organotypic brain models. The use of 3D human and animal brain cultures opens unprecedented perspectives for the development of neurobiology, molecular psychiatry and neurology. The high potential and flexibility of organotypic models, the increasing need for modeling various brain pathologies and the striving to establish causal mechanisms of disease allow us to assert that in the very near future 3D-models will experience rapid growth, development and widespread use.

Genetic predisposition to mental and neurodegenerative diseases may be due to mutations or polymorphisms of genes involved in the functioning and morphogenesis of the brain: the balance of monoamines and the action of navigational molecules and their receptors. The urokinase-type plasminogen activator receptor (uPAR) is an important participant in the processes that regulate neurogenesis. In particular, uPAR regulates the growth trajectory of axons. An increase in the level of soluble urokinase-type plasminogen activator receptor (suPAR) is observed in patients with schizophrenia compared with the healthy population. On the contrary, in patients with bipolar disorder in the manic and depressive phases, as well as in patients suffering from Alzheimer's disease, uPAR levels decrease. Molecules of the cadherin superfamily are involved in the formation and development of the nervous system, the transmission of intercellular signals, and the regulation of nerve cell lasticity. Studies have shown that changes in the CDH12, CDH13, CDH18, and CDH23 genes are associated with the development of schizophrenia, while CDH7, CDH13 and CDH18 are associated with the development of bipolar disorder, and N-cadherin and CDH13 are associated with the development of Alzheimer's disease. Adiponectin is a hormone secreted by adipose tissue. One of the adiponectin receptors, AdipoR2, stimulates neuronal plasticity and inhibits inflammation and oxidative stress. Patients with schizophrenia show increased levels of adiponectin, which plays a unique pro-inflammatory role in this model. In patients with bipolar disorder, there is a decrease in adiponectin levels during the depressive phase. In patients with Alzheimer's disease, a decrease in adiponectin levels contributes to the progression of the disease and accelerates the onset of cognitive impairment. Understanding the role of navigational molecules, in particular urokinase, T-cadherin, and their ligands (adiponectin, etc.) in the processes of morphogenesis, leading to incorrect laying of the brain, will make it possible not only to predict the likelihood of developing mental disorders, but also to carry out their timely prevention, determine the most appropriate therapeutic strategy depending on the form of the disease, and to develop efective methods of etiotropic and pathogenetic therapy.

Genetic technologies open up opportunities for studying the molecular basis of a wide range of hereditary pathologies, including mental disorders. Modeling certain genomic variants in cellular and animal models allows us to establish their functional significance and potential mechanisms of involvement in the disease progression, as well as lays the material basis for the development and testing of promising drugs. Here, in this study, we created the first line of transgenic mice carrying the P654L (rs139336954) mutation in the Plxna3 nerve tissue morphogenesis protein and studied their cognitive and behavioral characteristics. The Plxna3 protein, together with the Nrp1/Nrp2 co-receptor, detects signals from the repellent molecules Sema3a and Sema3f and determines the direction of cell migration and nerve fiber growth, the processes that are crucial for the proper development of the finely tuned nervous system. According to bioinformatic analysis, this mutation alters the structure of the extracellular domain of Plxna3, which could potentially disrupt the reception of Sema3a and/or Sema3f. Studies of the behavior of mice carrying the Plxna3-P654L (rs139336954) mutation have revealed increased anxiety, a high degree of orderliness, and reduced sensitivity to external stimuli, which could potentially be interpreted as symptoms of obsessive-compulsive personality disorder. No significant macroscopic or histological differences in brain structure were detected between the control and experimental groups. In this study, we draw attention for the first time to the genomic variant rs139336954 in the Plxna3 gene as a potential cause of obsessive-compulsive personality disorder and propose a novel transgenic model organism for studying the pathogenesis of this disease.