The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools

Author(s):Show less -

Marinho, Luciana Simoes Rafagnin ; Chiarantin, Gabrielly Maria Denadai ; Ikebara, Juliane Midori ; Cardoso, Debora Sterzeck ; de Lima-Vasconcellos, Theo Henrique ; Higa, Guilherme Shigueto Vilar ; Ferraz, Mariana Sacrini Ayres ; De Pasquale, Roberto ; Takada, Silvia Honda ; Papes, Fabio ; Muotri, Alysson R. ; Kihara, Alexandre Hiroaki

• Document type: Journal article
• Source: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY; v. 144, p. 10-pg., 2023-03-17.

Abstract

The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepres-sants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyper-activity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale tran-scriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids. (AU)

• FAPESP's process: 19/17892-8 - Degeneration and development of the nervous system: the role of epigenetic processes
• Grantee: Alexandre Hiroaki Kihara
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/16268-6 - Impact of neuroinflammation and the participation of the gut-brain axis in myelination in a rodent model of neonatal anoxia combined with perinatal inflammation by maternal immune activation
• Grantee: Silvia Honda Takada
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/11451-7 - Pitt-Hopkins Syndrome: studies on pathophysiology and genetic therapy using patient-derived cells and cerebral organoids
• Grantee: Fabio Papes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/02035-0 - Descriptive and functional analysis of the IP3R1 receptor in the pathology of retinitis pigmentosa using C3H/HeJ mice model
• Grantee: Théo Henrique de Lima Vasconcellos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/11969-9 - The role of IP3R1 in neuroinflammation triggered by retinitis pigmentosa
• Grantee: Théo Henrique de Lima Vasconcellos
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/11667-0 - Cellular and electrophysiological changes in the hippocampus caused by neurodegenerative processes related to neonatal anoxia and temporal lobe epilepsy
• Grantee: Alexandre Hiroaki Kihara
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/15024-9 - Information flow in neuronal networks of networks: oscillations, criticality and electrical synapses
• Grantee: Mariana Sacrini Ayres Ferraz
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/17329-3 - Characterization of the interneurons population and in vivo cortical and hippocampal electrophysiological activity of adult rats submitted to neonatal anoxia
• Grantee: Juliane Midori Ikebara
• Support Opportunities: Scholarships in Brazil - Doctorate