Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 22, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2025598118
Keywords
neurexin; synapse formation; schizophrenia; NMDA receptor; synaptic transmission
Categories
Funding
- National Institute of Mental Health (NIMH) [5U19MH104172, MH122519, 2U24MH068457]
- National Institute of Child Health and Human Development Postdoctoral Fellowship [F32HD078051]
- Katharine McCormick Advanced Postdoctoral Fellowship Fund
- University of Massachusetts Amherst Faculty Startup Fund
- National Institutes of Mental Health [F30MH108321]
- R00 grant [R00 AG054616]
- Stanford Schizophrenia Genetics Research Fund
- NIMH [MH59571, MH61675, MH67257, MH59588, MH59565, MH59587, MH59566, MH59586, MH60870, MH60879]
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Heterozygous NRXN1 deletions are associated with schizophrenia and other neurodevelopmental disorders, causing impaired neurotransmitter release in human neurons. However, mouse neurons with NRXN1 deletions did not show the same impairment, suggesting a human-specific phenotype. The deletions also led to increased levels of CASK and characteristic gene-expression changes, highlighting the potential for future drug discovery targeting NRXN1 deletions.
Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.
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