Zebrafish as a tool to study schizophrenia-associated copy number variants

Abstract

Schizophrenia remains one of the most debilitating human neurodevelopmental disorders, with few effective treatments and striking consequences felt by individuals, communities and society as a whole. As such, there remains a critical need for further investigation into the mechanistic underpinnings of schizophrenia so that novel therapeutic targets can be identified. Because schizophrenia is a highly heritable disorder, genetic risk factors remain an attractive avenue for this research. Given their clear molecular genetic consequences, recurrent microdeletions and duplications, or copy number variants (CNVs), represent one of the most tractable genetic entry points to elucidating these mechanisms. To date, eight CNVs have been shown to significantly increase the risk of schizophrenia. Although rodent models of these CNVs that exhibit behavioral phenotypes have been generated, the underlying molecular mechanisms remain largely elusive. Over the past decades, the zebrafish has emerged as a powerful vertebrate model that has led to fundamental discoveries in developmental neurobiology and behavioral genetics. Here, we review the attributes that make zebrafish exceptionally well suited to investigating individual and combinatorial gene contributions to CNV-mediated brain dysfunction in schizophrenia. With highly conserved genetics and neural substrates, an ever-expanding molecular genetic and imaging toolkit, and ability to perform high-throughput and high-content genetic and pharmacologic screens, zebrafish is poised to generate deep insights into the molecular genetic mechanisms of schizophrenia-associated neurodevelopmental and behavioral deficits, and to facilitate the identification of therapeutic targets.

Alterações Genotóxicas, Citotóxicas E Mutagênicas: Um Conteúdo a Ser Ilustrado E Trabalhado No Ensino Médio

“…Schizophrenia is a debilitating disorder characterized by disorganized psychiatric thinking, disorientation, hallucinations, illusions and motivational decline (18,48,51).…”

“…Hortaliça 101, 102 Hylocereus 5,56,57,112 Índice Remissivo T TCL 5,8,82,83,84,85,86,88 Tecidos vegetais 5,45,47,48,49,50,51,52,53 Telomerase 5,72,73,76,77,78,79,80,81 Telômeros 5,7,72,73,75,76,77,78,79 Tirosina Quinase 15 V Variabilidade 5,22,23,26,27,55,56,57,58,62,75,103,110,150…”

“…Neurological Disorders 5, 114, 129 P Produção 5,23,26,57,59,79,83,90,91,92,96,97,98,99,107,112 Pureza 5,7,44,45,46,48,49,50,51,52,60,62,66 R Radiologia 7,37,38,40,41,42 Reações a drogas 5,33,34 RNA 5,7,60,61,62,63,64,65,66,67,68,69,70,71,77,…”

Towards Modeling Anhedonia and Its Treatment in Zebrafish

“…In line with this, as already mentioned, zebrafish possess a generally similar brain architectonics to that of mammals ( Wullimann et al, 1996 ), including the reward circuits and shared neurotransmitters and hormones ( Panula et al, 2010 ) traditionally associated with anhedonia states. Moreover, zebrafish models have also been developed for several common CNS disorders with frequent anhedonic phenotypes, including depression ( Fonseka et al, 2016 ; de Abreu et al, 2018 ) and schizophrenia, as well as for chronic stress ( Demin et al, 2019 ; Gawel et al, 2019 ; Campbell and Granato, 2020 ; Costa et al, 2021 ). In addition, zebrafish also offer several clear advantages to study anhedonia and its therapy.…”

Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish

“…Excellent research with RNA-seq, which in addition highlights the suitability of zebrafish to study the implication of environmental factors in ASD-risk, was performed by Lee et al They exposed embryos to valproic acid—known to induce autism-like effects—and further performed RNA-seq, finding a direct correlation between zebrafish transcriptome and several ASD-associated genes [ 272 ]. This technique may also be useful to assess genetic compensation among individuals with phenotypic variability [ 273 ].…”