In a collaborative effort between the Lieber Institute for Brain Development (LIBD), the Hiroshima City Hospital in Japan, and various institutions in the US, researchers studied the gene NKCC1, a membrane-bound molecule involved in both brain development and nerve cell function. Looking at both postmortem human brain tissue and neuroimaging (fMRI) in live patients, our team discovered that certain variants of NKCC1 may play a role in the development of schizophrenia. The results of our work were published April 2, 2014 in The Journal of Neuroscience.
NKCC1 interacts with the brain’s primary inhibitory neurotransmitter, GABA. Neurotransmitters pass signals between brain cells, facilitating the brain’s vast communication network, and are either excitatory to stimulate the brain or inhibitory to balance the electrophysiological activity of the brain. GABA is the main inhibitory neurotransmitter in adults, but is excitatory during early brain development. NKCC1 enables GABA to effectively “switch” from excitatory to inhibitory, a process crucial to healthy brain development.
Abnormalities in GABA signaling have long been associated with schizophrenia and in earlier research, Thomas M. Hyde, M.D., Ph.D., Chief Operating Officer at LIBD, and colleagues examined the expression (“transcription”) of NKCC1 and three other molecules that are part of the machinery of GABA signaling (GAD67, GAD25 and KCC2). They found increased GAD25/GAD67 and NKCC1/KCC2 ratios in individuals with schizophrenia, reflecting a potentially under-developed GABA system.
“Together,” report the scientists, “these pre-clinical and clinical results suggest that variation in NKCC1 may increase risk for schizophrenia.” They go on to report that, “Because there are well-known molecules that block NKCC1 activity … NKCC1 might be a reasonable target for drug development in schizophrenia.”
In the current study, Dr. Hyde, with collaborators Drs. Yukitaka Morita, Amanda Law and others, characterized the entire human NKCC1 transcriptome for the first time. They then looked at how variants of messenger RNA from the NKCC1 gene were expressed during the development of the dorsolateral prefrontal cortex (DLPFC) region of the brain. The researchers compared postmortem human brain tissue from 45 patients with schizophrenia to 48 healthy controls. Additionally, they looked at tissue from 91 non-psychiatric control samples, ranging in age from 14 weeks in gestation to 78 years, to measure NKCC1 expression throughout the lifespan.
For the portion of the study that involved examining brain activity in live subjects, the researchers gathered data from the Clinical Brain Disorders Branch Sibling Study at the National Institute of Mental Health, which was directed by Daniel R. Weinberger, M.D., Director and CEO of LIBD and worked with 128 nuclear families with genetic susceptibility for schizophrenia as well as 313 healthy subjects. They analyzed brain activity while study participants completed working memory tasks during fMRI brain scans.
The researchers found that expression of the variants NKCC1b and 1-2a was decreased in individuals with schizophrenia. They further found that two polymorphisms (“SNPs”) led to reduced expression of NKCC1a and NKCC1b and that one of the two SNPs was associated with increased risk for schizophrenia, abnormal cognition, and alterations in brain activity in the live subjects during fMRI. “Together,” report the scientists, “these pre-clinical and clinical results suggest that variation in NKCC1 may increase risk for schizophrenia.” They go on to report that, “Because there are well-known molecules that block NKCC1 activity … NKCC1 might be a reasonable target for drug development in schizophrenia.”