A scientific team has shown that the release of neurotransmitters in the
brain is impaired in patients with schizophrenia who have a rare,
single-gene mutation known to predispose people to a range of
neurodevelopmental disorders.
Significantly, the results from the research with human-derived neurons
validated previous and new experiments that found the same major decrease in
neurotransmitter release and synaptic signaling in genetically engineered
human neurons with the same genetic variant - the deletion of neurexin 1
(NRXN1). NRXN1 is a protein-coding gene at the synapse, a cellular junction
that connects two nerve cells to communicate efficiently.
Both the research with human-derived and engineered human neurons also found
an increase in the levels of CASK, an NRXN1-binding protein, which were
associated with changes in gene expression.
"Losing one copy of this neurexin 1 gene somehow contributes to the etiology
or the disease mechanism in these schizophrenia patients," says molecular
neuroscientist ChangHui Pak, assistant professor of biochemistry and
molecular biology at the University of Massachusetts Amherst and lead author
of the research published in the Proceedings of the National Academy of
Sciences. "It causes a deficit in neural communication."
Pak is quick to add that although this single-gene mutation puts people at
risk for schizophrenia, autism, 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."
When she conducted most of the research, Pak was working in the Stanford
University lab of Thomas Südhof, a neuroscientist who shared the 2013 Nobel
Prize in Physiology or Medicine for helping to lay the molecular basis for
brain chemistry, including neurotransmitter release.
The research team obtained cell specimens from schizophrenia patients with
an NRXN1 deletion who donated samples to a national biorepository for
genetic studies of psychiatric disorders. Pak and colleagues converted the
participants' specimens into stem cells and then turned them into functional
neurons to study. "We're rewinding these cells back, almost like a time
machine - what did these patients' brains look like early on," Pak explains.
Labs at Stanford, Rutgers University and FUJIFILM Cellular Dynamics were
independently involved in the generation and analysis of neurons. For
comparison with the human-derived neurons, Pak and team also created human
neurons from embryonic stem cells, engineering them to have one less copy of
the NRXN1 gene. With engineered human neurons, they had previously noted the
neurotransmitter impairment and were interested in whether they would have
the same findings with 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," Pak says.
Notably, the researchers did not see the same decrease in neurotransmitter
release and other effects in engineered mouse neurons with analogous NRXN1
deletion. "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," Pak says.
Being able to reproduce the results is key to the development of drugs that
can better treat 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," Pak says. "We showed the field how this can be done."
Pak and her team are now continuing the research in the Pak Lab, supported
by a five-year, $2.25 million grant from the National Institute of Mental
Health. The scientists are using the latest stem cell and neuroscience
methodologies to explore the molecular basis of synaptic dysfunction in
schizophrenia and other neuropsychiatric disorders.
Reference:
Pak C, Danko T, Mirabella VR, et al. Cross-platform validation of
neurotransmitter release impairments in schizophrenia patient-derived
NRXN1-mutant neurons. PNAS. 2021;118(22). doi:
10.1073/pnas.2025598118