Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models

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.

Keywords: Huntington's disease; Parkinson's disease; neurodevelopmental diseases; organoids; synaptopathy.

Figure 1.

Schematic diagram depicting the molecular organization of excitatory and inhibitory synapses. The excitatory neurotransmitter glutamate is released from presynaptic neurons and binds to glutamate receptors NMDA and AMPA located in postsynaptic dendritic spines. Inhibitory neurotransmitters (gamma aminobutyric acid GABA or glycine) are released from presynaptic neurons and bind to GABA_A and glycine receptors clustered by gephyrin, the best-known inhibitory PSD protein. Synapse-organizing adhesion molecules include neurexins and neuroligins, cadherins, SLITRKs and others.

Figure 2.

Scheme of neurological disease modelling using cell reprogramming technology. ASD, autism spectrum disorders; SCZ, schizophrenia; BP, bipolar disorder; AD, Alzheimer's disease; PD, Parkinson's disease; HD, Huntington's disease; iPSCs, induced pluripotent stem cells; NPCs, neural progenitor cells.