Study reveals neurotransmitter releases impairments in schizophrenia patients

A research team revealed that neurotransmitter release in the brain is impaired in patients with schizophrenia who possess a rare, single-gene mutation that predisposes people to an array of neurodevelopmental disorders.

Study reveals neurotransmitter release impairments in schizophrenia patients
A neuron derived from a patient. Image Credit: University of Massachusetts Amherst.

The findings of the research based on human-derived neurons validated former and new experiments that identified the same significant decrease in neurotransmitter release and synaptic signaling in genetically engineered human neurons with the same genetic variant—the removal of neurexin 1 (NRXN1).

NRXN is a protein-coding gene found at the synapse, which is a cellular junction connecting two nerve cells to communicate effectively.

The research with human-derived and engineered human neurons identified an increase in the levels of CASK, an NRXN1-binding protein, associated with variations in gene expression.

Losing one copy of this neurexin 1 gene somehow contributes to the etiology or the disease mechanism in these schizophrenia patients. It causes a deficit in neural communication.”

ChangHui Pak, Study Lead Author, Molecular Neuroscientist, and Assistant Professor of Biochemistry and Molecular Biology, University of Massachusetts Amherst

The findings of the study have been published in the Proceedings of the National Academy of Sciences journal.

Pak also adds that even when the single gene mutation places people at risk of autism, schizophrenia, Tourette syndrome, and other neuropsychiatric disorders, “at the end of the day, we don’t know what causes schizophrenia. This variant gives us insight into what cellular pathways would be perturbed among people with schizophrenia and a lead to study this biology.”

Most parts of the research were conducted by Pak at the Stanford University lab of Thomas Südhof, a neuroscientist who shared the 2013 Nobel Prize in Physiology or Medicine for assisting to lay the molecular basis for brain chemistry, which includes the area of neurotransmitter release.

The scientists collected cell specimens from schizophrenic patients with an NRXN1 deletion who contributed samples to a national biorepository for genetic studies of psychiatric disorders. Pak and associates transformed the specimens from the participants into stem cells and later converted them into functional neurons for assessment.

We’re rewinding these cells back, almost like a time machine—what did these patients’ brains look like early on.”

ChangHui Pak, Study Lead Author, Molecular Neuroscientist, and Assistant Professor of Biochemistry and Molecular Biology, University of Massachusetts Amherst

The generation and the analysis of the neurons were done independently by the labs at Stanford, Rutgers University, and FUJIFILM Cellular Dynamics. To compare them with human-derived neurons, Pak and colleagues created human neurons from embryonic stem cells and designed them to have one less copy of the NRXN1 gene.

The researchers were interested in knowing if they could identify the same neurotransmitter impairment noted previously in engineered human neurons in patient-derived neurons.

It was good to see the consistent biological finding that indeed the neurexin 1 deletion in these patients actually does mess up their neuronal synaptic communication, and secondly that this is reproducible across different sites whoever does the experiment.”

ChangHui Pak, Study Lead Author, Molecular Neuroscientist, and Assistant Professor of Biochemistry and Molecular Biology, University of Massachusetts Amherst

The research team specifically did not find a similar decrease in neurotransmitter release and other impacts in engineered mouse neurons with similar NRXN1 deletion. Pak adds, “What this suggests is there is a human-specific component to this phenotype. The human neurons are particularly vulnerable to this genetic insult, compared to other organisms, adding to the value of studying human mutations in human cellular systems.”

The ability to reproduce the findings is vital for drug development, which can enhance the treatment of schizophrenia. “Everything was done blindly and at different sites. We wanted to not only learn about the biology but also be at the top of our game to ensure rigor and reproducibility of these findings. We showed the field how this can be done,” Pak further stated.

Source:
Journal reference:

Pak, C., et al. (2021) Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2025598118.

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