Genetic link to schizophrenia

The human brain continues to develop and form new connections from birth until as late as the mid-20s. During this time, billions of connections are made and broken as the brain develops the architecture required for learning, memory, language, emotion and many other brain functions. Disruptions in how the brain forms connections during infancy and early childhood can severely impair growth and negatively affect brain functions. Neurodevelopmental disorders such as autism spectrum disorders, Down syndrome, fragile X syndrome, and schizophrenia are all believed to result from disrupted brain connectivity during development. For some diseases, such as fragile X syndrome, a single gene mutation dramatically affects brain development. In contrast, many autism spectrum disorders are believed to result from a mosaic of minor gene mutations that synergistically affect brain development. For decades, researchers believed that such large-scale alterations in brain connectivity left almost permanent brain dysfunction that could not be reversed. However, a recent study has found that that is not always the case. Disruptions in the brain connections can be reversed in some circumstances. This study, published in Neuron, found that symptoms of schizophrenia that arose during the early years of brain development could be reversed in the later years of adulthood.


Neuregulin-1 (NRG-1) is a gene that helps regulate synaptic plasticity, and mutations in NRG-1 have been found in patients with schizophrenia. Researchers have found that the prefrontal cortex expresses much higher levels of NRG-1 in humans with schizophrenia. Because of this, researchers at the Medical College of Georgia developed a genetically modified mouse that also expressed abnormally high levels of NRG-1 in the brain. Surprisingly, these mice had many of the same symptoms observed in humans with schizophrenia: hyperactivity, slow learning and memory lapse. The researchers were then able to use a genetic trick to control the levels of NRG-1 in the brain by administering an antibiotic called doxycycline. In this way, the mice developed from birth with increased NRG-1 levels and developed schizophrenia-like behaviors. Then, when the mice were adult, the researchers gave doxycycline to the mice and lowered the NRG-1 brain levels back to normal. Amazingly, when NRG-1 levels were restored in ‘adulthood,’ the schizophrenia-like symptoms were gone! Reducing NRG-1 brain levels rescued the behavioral deficits in the mice and restored proper synaptic function.


In a separate set of experiments, NRG-1 brain levels were kept normal with doxycycline in the mice during development. When the mice were fully grown, the researchers discontinued doxycycline treatment, which caused the NRG-1 levels to rise in the brain. Interestingly, the adult mice developed schizophrenia-like symptoms! Together, these findings demonstrate that, although schizophrenia is a neurodevelopmental disease, it may be possible to reverse the behavioral deficits in adults. Unfortunately, there is not yet any cure for neurodevelopmental disorders. However, this study opens up the possibility of developing treatments for developmental disorders that may be beneficial even in adulthood.