Establishing a stem cell-based functional characterization of NRXN1-mutations from psychosis patients

2016 Seed Grant
Kristen J. Brennand, Ph.D.
Icahn School of Medicine at Mount Sinai

Deletions in the Neurexin-1 (NRXN1) gene can lead to autism and schizophrenia. Patients with NRXN1 mutations can present with a surprising variety of clinical outcomes (including diagnosis, severity, prognosis and age-of-onset), but it remains unknown why the effects of some NRXN1 mutations are stronger than others. Because of practical and ethical constraints, there is very limited brain tissue from patients with these mutations available for study. Moreover, mouse models do not permit researchers to study how and why some NRXN1 deletions have more deleterious effects in patients. To address these experimental limitations, we have reprogrammed skin cells from patients with deletions in the NRXN1 gene into human induced pluripotent stem cells and subsequently differentiated these stem cells into neurons. We propose to apply a novel sequencing approach in these patient-derived neurons, allowing us to understand which of the >1000 predicted isoforms of NRXN1 are most perturbed in patient-derived neurons. Once we understand which isoforms are most affected, we propose to restore their expression to normal levels, in order to ascertain the functional effects of perturbing, and restoring, NRXN1 in human neurons. This work may identify novel therapeutic points of intervention to delay the onset or reduce the severity of symptoms in individuals with NRXN1 deletions.

Other Grants

Sarah C. Goetz, Ph.D., Duke University
Uncovering a Novel Role for Primary Cilia in Eph/Ephrin Signaling in Neurons
2022 Seed GrantSarah C. Goetz, Ph.D. Duke University Women’s Council Seed Grant Primary cilia are tiny projections from cells that function like an antenna- they receive and may also send…
Erin M. Gibson, Ph.D., Stanford University
Circadian Regulation of Oligodendroglial Senescence and Metabolomics in Aging
2022 Seed GrantErin M. Gibson, Ph.D.Stanford University The brain consists of two main classes of cells, neurons and glia. Glia make-up more than half of the cells in the brain…
Yvette Fisher, Ph.D., University of California, Berkeley
Dynamic Modulation of Synaptic Plasticity During Spatial Exploration
2022 Seed GrantYvette Fisher, Ph.D.University of California, Berkeley The Virginia (Ginny) & Roger Carlson Seed Grant Cognitive flexibility is critical for appropriately adjusting thoughts and behaviors to meet changing demands…
Byoung Il Bae, Ph.D., University of Connecticut
Unique Vulnerability of Developing Human Cerebral Cortex to Loss of Centrosomal Protein
2022 Seed GrantByoung Il Bae, Ph.D.University of Connecticut Carl & Marilynn Thoma Foundation Seed Grant The cerebral cortex is the largest and outermost part of the human brain. It is…