Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons

Abstract

Schizophrenia (SCZ) and autism spectrum disorder (ASD) are genetically and phenotypically complex disorders of neural development. Human genetic studies, as well as studies examining structural changes at the cellular level, have converged on glutamatergic synapse formation, function, and maintenance as common pathophysiologic substrates involved in both disorders. Synapses as basic functional units of the brain are continuously modified by experience throughout life, therefore they are particularly attractive candidates for targeted therapy. Until recently we lacked a system to evaluate dynamic changes that lead to synaptic abnormalities. With the development of techniques to generate induced pluripotent stem cells (iPSCs) from patients, we are now able to study neuronal and synaptic development in cells from individual patients in the context of genetic changes conferring disease susceptibility. In this review, we discuss recent studies focusing on neural cells differentiated from SCZ and ASD patient iPSCs. These studies support a central role for glutamatergic synapse formation and function in both disorders and demonstrate that iPSC derived neurons offer a potential system for further evaluation of processes leading to synaptic dysregulation and for the design and screening of future therapies.

Keywords: Glutamatergic neurons; IPSCs; Neural development; Neurodevelopmental disorders; Synapses.

Fig. 1.

Structural changes in human postmortem studies (a) and iPSC generated neurons (b). Human postmortem studies demonstrate decreased synaptic spines in schizophrenia. In neurons derived from schizophrenia patients, there are fewer spines and presynaptic terminals. In autism spectrum disorder patients (ASD), postmortem brain studies demon-strate an increase in synaptic spine density as well as more immature synapses while in patient-iPSC derived neurons, there is decreased synaptic density and a more immature phenotype of dendritic spines.

Fig. 2.

Synaptic protein dysregulation in iPSC models of schizophrenia and autism. Studies to date demonstrate both presynaptic and postsynaptic protein expression changes in both schizophrenia and autism. Many of these proteins have been implicated in the disorders by genetic and postmortem studies.

Fig. 3.

iPSCs as a tool to identify therapeutic targets in autism spectrum disorder and schizophrenia. Analysis of multiple genetically distinct schizophrenia and autism patient-derived cells may demonstrate common cellular phenotypes. These are more likely to arise from disruption of common networks rather than a single genetic endpoint. Using a combination of human genetic analysis, postmortem studies and iPSC-derived neurons, a more focused network of related proteins or group of networks may be identified based on the intersection of data. In turn, iPSC-derived neurons can be used to independently manipulate those networks in an attempt to recapitulate the pathophysiology or rescue the phenotype before further study in animals and humans.