Advancing preclinical models of psychiatric disorders with human brain organoid cultures

Abstract

Psychiatric disorders are often distinguished from neurological disorders in that the former do not have characteristic lesions or findings from cerebrospinal fluid, electroencephalograms (EEGs), or brain imaging, and furthermore do not have commonly recognized convergent mechanisms. Psychiatric disorders commonly involve clinical diagnosis of phenotypic behavioral disturbances of mood and psychosis, often with a poorly understood contribution of environmental factors. As such, psychiatric disease has been challenging to model preclinically for mechanistic understanding and pharmaceutical development. This review compares commonly used animal paradigms of preclinical testing with evolving techniques of induced pluripotent cell culture with a focus on emerging three-dimensional models. Advances in complexity of 3D cultures, recapitulating electrical activity in utero, and disease modeling of psychosis, mood, and environmentally induced disorders are reviewed. Insights from these rapidly expanding technologies are discussed as they pertain to the utility of human organoid and other models in finding novel research directions, validating pharmaceutical action, and recapitulating human disease.

Neurexin dysfunction in neurodevelopmental and neuropsychiatric disorders: a PRIMSA-based systematic review through iPSC and animal models

“…While animal models are informative, translating these findings directly to humans can be uncertain. Additionally, hiPSC models, despite their sophistication, may not fully capture the intricacies of human brain development in vivo ( Dixon and Muotri, 2023 ).…”

Preservation of co-expression defines the primary tissue fidelity of human neural organoids

“…One exciting application for the use of neural organoid systems is the study of a wide-range of human neurological diseases using human in vitro models 52,53 , which critically depends on the in vivo fidelity of cell-types produced in organoids. Neural organoids have been used to model and investigate human disorders of neurodevelopmental 3,54 , neuropsychiatric [55][56][57] , and neurodegenerative [58][59][60] nature, as well as infectious diseases 28,61,62 . It is essential that organoid systems model in vivo cell-types with extreme fidelity to fully realize the therapeutic potential of human organoids and ensure findings in these in vitro models are not specific to potential artifactual or inaccurate in vitro biology.…”

Altered neuroepithelial morphogenesis and migration defects in iPSC-derived cerebral organoids and 2D neural stem cells in familial bipolar disorder

“…Earlier studies have utilized patient-derived iPSCs to create both 2D neuronal cultures and 3D brain organoids in order to elucidate the mechanistic basis of BD pathogenesis. Some of the most significant pathophysiological mechanisms identified thus far include ion channel dysfunction [ 25 , 26 ], impaired calcium signalling [ 27 , 28 ], mitochondrial dysfunction [ 29 , 30 ], inflammation [ 31 ], and neuronal hyperexcitability [ 32 , 33 ]. A recent study demonstrated that iPSC-derived cortical spheroids from BD patients exhibit smaller sizes, a lower proportion of neurons, and reduced neural network activity in comparison to control spheroids [ 34 ].…”