The neurons generated from every 22q11DS carrier in the study demonstrated a consistently less-than-normal voltage difference between the inner-facing and outer-facing sides of the cell membranes when the cells weren’t firing. A quiescent neuron’s cross-membrane voltage difference is called its resting membrane potential; it keeps the neuron poised to fire while preventing it from firing at random.
Cortical neurons derived from people with 22q11DS were more excitable, the study found. This is likely because of their abnormal resting membrane potential, Pasca said. The 22q11DS-derived neurons spontaneously fired four times as frequently as neurons derived from people in the control group. This altered resting membrane potential also led to abnormalities in calcium signaling in the 22q11DS neurons. Treating these neurons with any of three different antipsychotic drugs effectively reversed the defects in resting membrane potential and calcium signaling, and prevented these neurons from being so excitable.
The researchers also studied a gene called DGCR8, which has been suspected of being tied to schizophrenia. DGCR8 is one of scores of genes normally residing along a stretch of chromosomal DNA that’s deleted in a person with 22q11DS.
Knocking down DGCR8’s activity levels in the control neurons reproduced the weakened resting membrane potential and associated malfunctions seen in the 22q11DS neurons. Boosting the activity of the gene through genetic manipulation or by applying antipsychotic drugs to 22q11DS neurons largely restored that potential.
“DGCR8 is probably the main player in the cellular defects we observed,” Pasca said. Some of these defects are probably also present in some other forms of schizophrenia, he added.
“We can’t test hallucinations in a dish,” Pasca said. “But the fact that the cellular malfunctions we identified in a dish were reversed by drugs that relieve symptoms in people with schizophrenia suggests that these cellular malfunctions could be related to the disorder’s behavioral manifestations.”
There are undoubtedly many types of schizophrenia, he said. “But clinically, 22q11DS-related schizophrenia isn’t very different from other forms of schizophrenia. Some of the mechanisms we’ve identified here may turn out to apply to those more genetically or environmentally complex types of schizophrenia.”
Pasca is a member of Stanford Bio-X, the Stanford Maternal & Child Health Research Institute, and Stanford Wu Tsai Neurosciences Institute, and is a faculty fellow of Stanford ChEM-H.
Other Stanford co-authors of the study are former medical student Anna Krawisz, MD; former postdoctoral scholars Carleton Goold, PhD, Yishan Sun, PhD, and Masayuki Yazawa, PhD; former undergraduate student Julia Schaepe; former visiting researcher Kazuya Ikeda, MD; postdoctoral medical fellow Neal Amin, MD, PhD; postdoctoral scholar Min-Yin Li, PhD; basic life research scientist Noriaki Sakai, DVM, PhD; Seiji Nishino, MD, PhD, professor emeritus of psychiatry and behavioral sciences; Matthew Porteus, MD, professor of pediatrics; Jonathan Bernstein, MD, associate professor of pediatrics; Ruth O’Hara, PhD, professor of psychiatry and behavioral sciences; Joachim Hallmayer, MD, professor of psychiatry and behavioral sciences; and John Huguenard, PhD, professor of neurology.
Researchers at UCLA; Yonsei University College of Medicine in Seoul, South Korea; the National Institute of Mental Health; and the Novartis Institutes for Medical Research also contributed to the study.
The work was funded by the National Institutes of Health (grants R01MH107800, R01MH100900, R01MH085953, R37MH060233 and R01MH094714); the Behavioral and Brain Research Foundation; the New York Stem Cell Foundation; the MQ Foundation; the Stanford Wu Tsai Neurosciences Institute’s Brain Rejuvenation Project; the Stanford Human Brain Organogenesis Program; the Uytengsu Family Research Fund; the Kwan Research Fund; the California Institute for Regenerative Medicine; the National Research Foundation of Korea; the National Science Foundation; the Feldman Gift Fund; the Maternal and Child Health Research Institute; the Autism Science Foundation; a Stanford Medicine Dean’s Fellowship; the Howard Hughes Medical Institute; Stanford Bio-X; and the Ministry of Science, ICT & Future Planning in Korea.