The mammalian target of rapamycin (mTOR) is an important molecular regulator of cell growth and proliferation. Brain mTOR activity plays a crucial role in synaptic plasticity, cell development, migration and proliferation, as well as memory storage, protein synthesis, autophagy, ion channel expression and axonal regeneration. Aberrant mTOR signaling causes a diverse group of neurological disorders, termed ‘mTORopathies’. Typically arising from mutations within the mTOR signaling pathway, these disorders are characterized by cortical malformations and other neuromorphological abnormalities that usually co-occur with severe, often treatment-resistant, epilepsy. Here, we discuss recent advances and current challenges in developing experimental models of mTOR-dependent epilepsy and other related mTORopathies, including using zebrafish models for studying these disorders, as well as outline future directions of research in this field.

Antimicrobial drugs represent a diverse group of widely utilized antibiotic, antifungal, antiparasitic and antiviral agents. Their growing use and clinical importance necessitate our improved understanding of physiological effects of antimicrobial drugs, including their potential effects on the central nervous system (CNS), at molecular, cellular, and behavioral levels. In addition, antimicrobial drugs can alter the composition of gut microbiota, and hence affect the gut–microbiota–brain axis, further modulating brain and behavioral processes. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a powerful model system for screening various antimicrobial drugs, including probing their putative CNS effects. Here, we critically discuss recent evidence on the effects of antimicrobial drugs on brain and behavior in zebrafish, and outline future related lines of research using this aquatic model organism.

Background/Objectives: Chronic stress and neuroinflammation (promoted by micro- and astroglia) represent key factors in affective pathogenesis. Complementing rodent models, zebrafish (Danio rerio) are widely used in experimental modeling of affective disorders. Here, we examined the effects of chronic treatment with two distinct anti-inflammatory drugs, minocycline and nimesulide, on behavior and neuroinflammation-related biomarker genes in the zebrafish chronic unpredictable stress (CUS) model. Methods: Following two-week CUS with or without drug treatment, fish were assessed using the novel tank test for anxiety-like behavior, and the zebrafish tail immobilization (ZTI) test for depression-like behavior. Results: A 14-day treatment with minocycline (50 mg/L) reduced general motor activity and brain expression of both pro-inflammatory (nos2a) and anti-inflammatory (arg1) microglial biomarker genes, as well as upregulated the anti-inflammatory astrocytic marker s100a10. In CUS-exposed fish, this treatment attenuated depression-like ZTI immobility behavior and downregulated both pro-inflammatory (nos2a, cox2) and anti-inflammatory (arg1, ptx) glial biomarkers compared to the stress-only control. In contrast, one-week nimesulide treatment during CUS produced an anxiolytic-like effect and normalized the expression of stress-induced pro-inflammatory glial biomarkers cox2 and il1β. Conclusions: Overall, our findings suggest that the two anti-inflammatory drugs tested modulate behavioral and molecular responses to chronic stress in zebrafish, with minocycline demonstrating broader anti-neuroinflammatory and antidepressant-like effects, and nimesulide exhibiting more specific anxiolytic-like properties in this model.

Scientific relevance. Since fiscal and regulatory constraints substantially limit bioscreening in rodent models, a wider implementation of additional alternative models in preclinical studies of medicines is gaining momentum. These alternative models include aquatic vertebrates, such as zebrafish (Danio rerio).Aim.The study aimed to examine zebrafish models in terms of their performance in preclinical studies, their current uses, the challenges and opportunities in the field, and strategic directions for the development of preclinical testing in zebrafish.Discussion.Here, the authors summarise the key zebrafish tests that are currently used to assess a wide range of small molecules for their general and endocrine toxicity and effects on the survival of embryos and larvae. The review discusses the strengths and weaknesses of zebrafish models for preclinical testing of neurotropic agents. Additionally, the authors overview various methodological approaches to improving zebrafish toxicity testing. Overall, the use of zebrafish models is gradually becoming internationally established for laboratory testing of small molecules.Conclusions.A wider implementation of zebrafish models in pharmaceutical research and preclinical testing as an additional alternative to rodents, particularly in Russia, may significantly accelerate the development of novel medicinal products and foster a more comprehensive and adequate assessment of the biological risks associated with chemical substances.