MODELING BIPOLAR DISORDER IN MICE THROUGH NEURAL PRECURSOR CELLS DERIVED FROM PATIENT OLFACTORY NEUROEPITHELIUM

Bipolar disorder (BD) is a highly heritable psychiatric illness with a lifetime prevalence of 1-3%. It is a multifactorial condition involving genetic and environmental factors. Lithium is the gold standard treatment, although 40-50% of patients show inadequate responses or severe side effects. The scarcity of experimental BD models hampers the identification of novel biomarkers and treatments. Therefore, we aim to develop a humanized murine BD model using human olfactory neuroepithelium (ONE) cells and assess its face, construct, and predictive validity, particularly regarding lithium response.
ONE neural progenitor cells from control donors and BD type-I patients, which respond or do not respond to lithium treatment based on the ALDA scale, were grafted into a neurogenic niche in rodents. Mania-like and depressive-like behaviors were assessed 4 weeks after implantation as correlates of BD-like phenotype. Lithium was administered via chow for 3 weeks before behavioral testing. At the endpoint, brains were collected for immunofluorescence and electron microscopy analyses.
Animals grafted with ONE cells from patients develop a BD-like phenotype (depressive-like behavior and motor hyperactivity) 4 weeks after implantation. Strikingly, this phenotype is specifically reversed after chronic lithium treatment in animals grafted with ONE cells from lithium responders. Additionally, immunohistological studies showed that 75-80% of these human ONE cells expressed mature GABAergic neuron markers and were integrated into the mouse neuronal circuit receiving synaptic contacts.
These results indicate that the model would be suitable for studying BD neurobiology, identifying predictive biomarkers of therapeutic response, and evaluating treatment efficacy, while opening avenues for personalized medicine.