The abnormal behavior of two genes (BDNF and DTNBP1) is related to the underlying cause of schizophrenia, providing a new target for schizophrenia treatment, according to research led by scientists from Duke-NUS Graduate Medical School Singapore (Duke-NUS). The study was published online in the journal Biological Psychiatry and reported in Drug Discovery & Development
Schizophrenia, a devastating mental disorder, affects nearly 1 percent of the total human population. The primary cause of the disorder involves impaired brain development that eventually leads to imbalanced signals in the brain. This imbalance may cause hallucinations and paranoia in people with schizophrenia.
As senior author Assistant Professor Shawn Je, from the Neuroscience and Behavioral Disorders Programme at Duke-NUS, explained, "We wanted to understand the mechanism by which the brain circuit operates. In particular, we wanted to understand the ability of a specific type of cell in the brain, termed interneurons, to modulate brain network activity to maintain a balance in brain signalling."
Dr. Je and his team analyzed signaling activity in neuronal cultures that either did not have the DTNBP1 gene or had lowered levels of the gene. They found that reduced DTNBP1 levels and genetic disruptions of DTNBP1 in mice resulted in schizophrenia-like behaviors. When using multiple model systems, they discovered that the low levels of DTNBP1 caused dysfunctional interneurons and over-activated neuronal network activity. Lowering levels of DTNBP1 also reduced the levels of the secreted protein molecule, BDNF.
The researchers showed that BDNF was one of the most important factors that regulate the development of a normal brain circuit. BDNF plays an important role in the interneurons’ ability to connect to the brain. Interneurons receive BDNF via a transport system controlled by DTNBP1. Think of the process as the delivery of a parcel: DTNBP1 acts as the driver of the delivery van. Without the driver, the parcel BDNF cannot be delivered to the required destination. If BDNF is lacking, there is abnormal circuit development and brain network activity observed in schizophrenia patients. Dr. Je and his team also found that when BDNF levels were restored, brain development and activity were rescued and returned to more normal levels, despite the absence of DTNBP1.
DTNBP1 and BDNF have been singled out as risk genes for schizophrenia in studies before, but this is the first study to demonstrate that the two work together. Highlighting the importance of the abnormal delivery of BDNF has offered much insight into how the brain network develops. The study also offers possibilities for new treatments for schizophrenia based on enhancing BDNF levels.
Dr. Je plans to do a follow-up study to determine whether these findings are viable in an animal model. If he and his colleagues are successful, it could mean that changing the imbalance in the brain circuits of schizophrenia patients could bring us closer to developing a treatment.