Abstract
Synaptic dysfunction in CNS disorders is the outcome of perturbations in physiological synapse structure and function, and can be either the cause or the consequence in specific pathologies. Accumulating data in the field of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia and bipolar disorder, point to a neurodevelopmental origin of these pathologies. Due to a relatively early onset of behavioural and cognitive symptoms, it is generally acknowledged that mental illness initiates at the synapse level. On the other hand, synaptic dysfunction has been considered as an endpoint incident in neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's, mainly due to the considerably later onset of clinical symptoms and progressive appearance of cognitive deficits. This dichotomy has recently been challenged, particularly since the discovery of cell reprogramming technologies and the generation of induced pluripotent stem cells from patient somatic cells. The creation of ‘disease-in-a-dish’ models for multiple CNS pathologies has revealed unexpected commonalities in the molecular and cellular mechanisms operating in both developmental and degenerative conditions, most of which meet at the synapse level. In this review we discuss synaptic dysfunction in prototype neurodevelopmental and neurodegenerative diseases, emphasizing overlapping features of synaptopathy that have been suggested by studies using induced pluripotent stem-cell-based systems. These valuable disease models have highlighted a potential neurodevelopmental component in classical neurodegenerative diseases that is worth pursuing and investigating further. Moving from demonstration of correlation to understanding mechanistic causality forms the basis for developing novel therapeutics.
Highlights
Central nervous system (CNS) disorders are a group of diseases with significant socioeconomic impact and growing relevance due to the increase in life expectancy of the world population
We present evidence that support synaptopathy as a central feature of these pathologies and raise the intriguing hypothesis that defects in synaptic function may comprise an early and, possibly, triggering event in the pathogenesis of neurodevelopmental and neurodegenerative diseases
The remarkable feature of this differentiation process in vitro is that it mimics, to a large extent, human brain development. human induced pluripotent stem cells (hiPSCs) are directed to acquire a neuroectodermal fate where induction of a regional neuroepithelial phenotype is achieved by specific patterning factors that in turn prompt the expression of master regulatory transcription factors, characteristic for the desired type of neural progenitor cells (NPCs)
Summary
Central nervous system (CNS) disorders are a group of diseases with significant socioeconomic impact and growing relevance due to the increase in life expectancy of the world population. CNS disorders, traditionally dichotomized between early-onset neurodevelopmental and late-onset neurodegenerative diseases, are associated with dysfunction of neuronal activity due to perturbations at the synapse level [1]. They may be collectively regarded as diseases of the synapse or synaptopathies. The development of three-dimensional (3D) organoid cultures has created new possibilities for studying disease emergence and progression in the closest situation to the human brain [3] Due to these revolutionizing technologies it is possible to shed light into cellular and molecular mechanisms underlying neuronal dysfunction in patient cells and follow over time the emergence of disease phenotypes, those appearing early. The experimental challenges and limitations of using hiPSCbased models for understanding synaptic dysfunction in neurological diseases are considered, together with the potential of overcoming these significant drawbacks to gain a deeper understanding of disease mechanisms and develop effective therapeutic strategies
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