Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Abstract

The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.

Keywords: brain; cerebral cortex; developmental disorders; evolution; human; intellectual disability; modeling; neural; pluripotent stem cells; species.

Figure 1

The Genetics of Human FXS versus Mouse Models of FXS (A) The human FMR1 locus contains several primate-specific lnRNAs, FMR4, FMR5, and FMR6. ASFMR1 exists in both humans and mice. In FXS-affected individuals with a full mutation, most of these lncRNAs are also silenced. (B) Mouse models of FXS have been created through the insertion of a neomycin cassette into exon 5 (KO1) or the deletion of the promoter and exon 1 (KO2), leading to a lack of protein production in both KO1 and KO2. ASFmr1 expression is unknown in mouse models.

Figure 2

Comparison of Human Chromosome 21 and Mouse Models (A) Genes in human chromosome 21 have orthologous regions on three mouse chromosomes. (B) Schematic of chromosome 21 genes that are represented in three mouse models: Ts65Dn (the most widely studied mouse model), Dp16, and Tc1 (a transchromosomic mouse line)., ,

Figure 3

Human FXS Neurological and Behavioral Deficits that Are Represented in Mouse Models and/or Human Stem Cell Models Although FXS-affected individuals also exhibit reduced pre-pulse inhibition (PPI), mouse models show either increased or no change in PPI.

Figure 4

Human DS Neurological and Behavioral Deficits that Are Represented in Mouse Models and/or Human Stem Cell Models Increased GABAergic inhibition has not yet been shown in human DS.