Summary: Researchers report that neurotransmitter release is impaired in the brains of people with schizophrenia who carry a deletion in the neurexin 1 gene (NRXN1).
Source: UMass
A multidisciplinary team has demonstrated that a rare, single-gene mutation linked to neurodevelopmental disorders disrupts neurotransmitter release in neurons derived from schizophrenia patients.
The study found that neurons derived from people with schizophrenia who carry a heterozygous deletion in NRXN1 show a marked decrease in neurotransmitter release and weakened synaptic signaling. These patient-derived findings match earlier experiments in engineered human neurons that carried the same NRXN1 deletion. NRXN1 encodes a synaptic protein located at the junctions between nerve cells, where efficient communication depends on tightly regulated neurotransmitter release.
Both patient-derived and engineered human neurons displayed increased levels of the NRXN1-binding protein CASK, a change that correlated with shifts in gene expression patterns. These molecular and functional signatures point to disrupted synaptic machinery as a consequence of losing one NRXN1 allele.
“Losing one copy of this neurexin 1 gene contributes to the disease mechanism in these schizophrenia patients,” explains ChangHui Pak, assistant professor of biochemistry and molecular biology at the University of Massachusetts Amherst and lead author of the paper published in the Proceedings of the National Academy of Sciences. “It causes a deficit in neural communication.”
Pak emphasizes that while NRXN1 deletions increase risk for schizophrenia, autism, Tourette syndrome and other neuropsychiatric conditions, they do not fully explain the cause of schizophrenia. Instead, the NRXN1 variant provides a window into the cellular pathways likely perturbed in affected individuals and suggests specific targets for further biological study.
Much of the work was completed while Pak was at Stanford University in the lab of Thomas Südhof, who shared the 2013 Nobel Prize in Physiology or Medicine for elucidating molecular mechanisms of neurotransmitter release. For this study, the team obtained cell samples from schizophrenia patients with NRXN1 deletions through a national biorepository for psychiatric genetics. The researchers converted those patient cells into induced pluripotent stem cells and then differentiated them into functional neurons—essentially recreating early neural development to study synaptic function in a human cellular context.
Independent laboratories at Stanford, Rutgers University and FUJIFILM Cellular Dynamics participated in generating and analyzing these neurons. For comparison, the authors also created engineered human neurons from embryonic stem cells with a single-copy NRXN1 deletion. The same impairment in neurotransmitter release had been observed previously in those engineered neurons, and the current study confirms the effect in patient-derived cells.
“It was important to see the same biological outcome across different laboratories and cell sources,” Pak says. “The neurexin 1 deletion in these patients consistently disrupts neuronal synaptic communication, and the finding is reproducible across sites.”
Notably, comparable NRXN1 deletions in mouse neurons did not produce the same decrease in neurotransmitter release. Mouse neurons engineered by the same methods showed no significant impairment, suggesting a human-specific vulnerability to NRXN1 loss. This species difference highlights the importance of studying human mutations in human cellular systems when modeling human neuropsychiatric disease mechanisms.
Reproducibility across multiple laboratories and blinded analyses strengthens the confidence that NRXN1 haploinsufficiency produces a robust synaptic phenotype in human neurons. These rigorous cross-platform validations are essential if this cellular phenotype is to be used in drug discovery efforts aimed at treating schizophrenia and related disorders.
Pak and colleagues continue this line of research in the Pak Lab with support from a five-year, $2.25 million grant from the National Institute of Mental Health. The team is applying advanced stem cell techniques and neuroscience assays to further dissect molecular causes of synaptic dysfunction in schizophrenia and to identify candidate pathways for therapeutic intervention.
About this schizophrenia and genetics research news
Source: UMass
Contact: Patty Shillington – UMass
Image: The image is in the public domain
Original Research: Closed access.
“Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons” by ChangHui Pak. PNAS. DOI: 10.1073/pnas.2025598118
Abstract
Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons
Heterozygous NRXN1 deletions are the most common known single-gene mutation currently associated with schizophrenia and also increase risk for several neurodevelopmental disorders. Previous work showed that engineered heterozygous NRXN1 deletions impair neurotransmitter release in human neurons, implicating synaptic dysfunction as a pathophysiological mechanism. To support drug discovery efforts based on this observation, its robustness needed validation across platforms and genetic backgrounds.
This multicenter study tested patient-derived neurons and newly engineered human neurons, each carrying heterozygous NRXN1 deletions, using independent analyses performed at two laboratories. Neurons transdifferentiated from induced pluripotent stem cells derived from schizophrenia patients with NRXN1 deletions exhibited the same synaptic impairments as engineered NRXN1-deficient human neurons.
The synaptic deficits included a large reduction in spontaneous synaptic events, diminished evoked synaptic responses, and altered paired-pulse depression—measures that reflect impaired neurotransmitter release and synaptic efficacy. By contrast, mouse neurons with analogous Nrxn1 deletions did not show the same impairment, indicating a human-specific phenotype. NRXN1 deletions in human neurons reproducibly increased levels of the CASK protein and were associated with characteristic changes in gene expression.
In summary, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, providing a validated cellular phenotype that can guide future studies and therapeutic development for schizophrenia and related disorders.