Understanding the molecular basis of autism in a dish using hiPSCs-derived neurons from ASD patients

Hwang

et al. 2020

JCM

Self Cite

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.

Section: Introductionmentioning

confidence: 99%

Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes

Hwang

et al. 2020

JCM

Self Cite

“…Paşca and his team observed that the spheroids comprise distinct neuronal subtypes interspersed with astrocytes, and that this architecture closely mimics the in vivo physiology . Induced PSC‐derived brain organoids have also been used to reproduce the defective synaptic conductivity that is observed in autistic spectrum disorders . In one study, for example, up‐regulation of the transcription factor, the Forkhead box protein G1 (FOXG1), resulted in an overproduction of GABAergic neurons, which subsequently increased synaptogenesis and dendrite outgrowth .…”

Section: Unraveling the Causes Of Improper Neuronal Developmentmentioning

confidence: 98%

“…Brain organoids have also been used to model synaptogenesis and identify mechanisms that destabilize the process, thereby causing developmental disorders . For instance, Paşca and co‐workers investigated the migration of GABAergic (γ‐aminobutyric‐acid releasing) neurons from the ventral to dorsal forebrain in spheroids produced from human PSCs in the absence of ECM patterning factors .…”

Section: Unraveling the Causes Of Improper Neuronal Developmentmentioning

confidence: 99%

Brain Organoids: A New, Transformative Investigational Tool for Neuroscience Research

Ghaemi

McFee

et al. 2018

Adv. Biosys.

Brain organoids are self‐assembled, three‐dimensionally structured tissues that are typically derived from pluripotent stem cells. They are multicellular aggregates that more accurately recapitulate the tissue microenvironment compared to the other cell culture systems and can also reproduce organ function. They are promising models for evaluating drug leads, particularly those that target neurodegeneration, since they are genetically and phenotypically stable over prolonged durations of culturing and they reasonably reproduce critical physiological phenomena such as biochemical gradients and responses by the native tissue to stimuli. Beyond drug discovery, the use of brain organoids could also be extended to investigating early brain development and identifying the mechanisms that elicit neurodegeneration. Herein, the current state of the fabrication and use of brain organoids in drug development and medical research is summarized. Although the use of brain organoids represents a quantum leap over existing investigational tools used by the pharmaceutical industry, they are nonetheless imperfect systems that could be greatly improved through bioengineering. To this end, some key scientific challenges that would need to be addressed in order to enhance the relevance of brain organoids as model tissue are listed. Potential solutions to these challenges, including the use of bioprinting, are highlighted thereafter.

Neuroscience & Biobehavioral Reviews

“…Finally, with regard to pertinent treatments for neurodevelopmental disorders, it is important to consider the genetics of individual patients rather than the overall heterogeneous population, similar to what has been already achieved with chemotherapeutic strategies in cancer genomics for personalized medicine (Boyer et al, 2016;Hermens et al, 2006;Jellen et al, 2015;Lim et al, 2015;Riazuddin et al, 2017). Genetic factors are known to play a critical role in a variety of behaviors, including cognition and the pathogenesis of psychiatric illnesses (Bespalov et al, 2012;Bespalova and Buxbaum, 2003;Papaleo et al, 2012;Scheggia et al, 2018).…”

Section: The Importance Of Assessing Developmental Trajectoriesmentioning

confidence: 99%

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

Morè

Lauterborn

Papaleo

et al. 2020