June 03, 2007

Genes Common to Both Schizophrenia and Seizures May Cause Faulty "Check and Balance" Brain Activity

In an article in journal Neuron, research scientists revealed new functions of two genes important for human development and implicated in cancer, schizophrenia, and seizures. The genes are neuregulin-1 (NRG1) and its receptor, ErbB4.

The researchers say that these same genes also help keep a healthy balance between excitation and inhibition of brain cells in the prefrontal cortex. This "check and balance" for neuron activity provides insight into both schizophrenia and seizures, and the hope is that they will provide a new target for treatment of these disorders.

The researchers, led by Dr. Mei, chief of developmental neurobiology at the Medical College of Georgia (MCG), had previously shown that the genes are involved in an excitatory function at communication points (synapses) between neurons in the brain. There, the neurotransmitter glutamate excites cells to action.

"(Dr. Mei’s) findings help explain how a gene that is potentially causative in disorders like schizophrenia and bipolar disorder relate to a neurotransmitter that is critical for explaining the cognitive deficits associated with the illness," says Dr. Daniel R. Weinberger, director of the Genes, Cognition and Psychosis Program at the National Institute of Mental Health in Bethesda, Md.

Now, the researchers at MCG and Cold Spring Harbor Laboratory (CSHL) have identified a new function of NRG1 -- suppressing excitation, inhibiting the communication at synapses, by increasing the release of GABA, a major inhibitory neurotransmitter.

Dr. Mei says:

"Right beside the place where the excitatory synapse can be activated, there is also something that can suppress it. Now we have identified another novel target of neuregulin-1 which is the inhibitory synapse."

Together the findings reveal a check and balance for brain cell activity managed by neuregulin-1 in the brain’s prefrontal cortex, where complex reasoning and decisions about appropriate social behavior occur, he says.

The issue of journal neuron explores these genes' functions on both sides of the "checks and balances", delving into the effect of ErbB4 on glutamatergic synapse maturation and plasticity, as well as the effect of NRG1 on GABA release.

Below is the full press release from CSHL:

Cold Spring Harbor Laboratory (CSHL) researchers have identified a function of neuregulin1 (NRG1), a gene previously linked to schizophrenia but whose role in the disease was unknown. “We found that when this gene or this pathway is impaired,” explained CSHL’s Bo Li, “it starts a chain reaction negatively impacting synapses in the brain which contribute to the abnormal development of brain circuits and may lead to schizophrenia.”

By discovering the connections between genes and how they impact synapses and circuits in the brain, research is guiding the development of new strategies to diagnose and treat neurological disease. Published on May 24, 2007 in the journal Neuron, this latest research supports the hypothesis that schizophrenia is a disease that results from multiple factors, including genetic defects and developmental abnormalities in the brain. A lynchpin in the development of the disease is the brain’s neurotransmitter system known as the glutamate system. When the glutamate system is suppressed it leads to abnormal brain development and schizophrenic symptoms.

Unlocking the mystery of NRG1 and its critical function in the normal development of the glutamate system was the result of a unique combination of technologies at CSHL. Under the direction of CSHL’s Neuroscience Research Program Chair, Robert Malinow, M.D., Ph.D., researchers inform their study of diseased brains by the ongoing study of normal brains. “The ability to finally identify the functionality of NRG1 was possible here because of access to powerful technology that combined the ability to manipulate individual genes, to study the very structure of the glutamate synapse with a two-photon microscope, and to perform functional studies using electrophysiology.”

Li hopes that his research will stimulate more exploration of the functions of NRG1 in the brain. “This gene and its pathway also have implications for other neurological diseases such as bipolar disorder. Knowing the cellular and molecular mechanisms of NRG1, we can now more intensely study the impact on complex brain circuits that define the aberrant behavior of these diseases,” said Li.

The paper’s full citation is as follows: Bo Li, Ran-Sook Woo, Lin Mei, and Roberto Malinow.
The article summary is available online at http://www.neuron.org/content/article/abstract?uid=PIIS0896627307002607

CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.

Read Also the Press Release from MCG: Check and balance for neuron activity provides insight into schizophrenia, seizures
Source Abstracts:
Neuregulin-1 Enhances Depolarization-Induced GABA Release
The Neuregulin-1 Receptor ErbB4 Controls Glutamatergic Synapse Maturation and Plasticity

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