NIH Scientists Identify Link Between Brain Systems Implicated in Schizophrenia

Scientists at the National Institutes of Health have deciphered the complex relationship between three distinct brain circuits implicated in schizophrenia. The researchers determined that one brain circuit acts through an intermediary brain circuit. The intermediary circuit acts like a volume control knob, turning up the electrical activity of still another brain circuit, or turning it down.

The finding suggests that schizophrenia could result from a malfunction anywhere in the link between these three brain circuits.

“This discovery lays the groundwork for studies that may lead to more effective treatments for schizophrenia,” said Duane Alexander, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH institute where the research was undertaken. “Theoretically, each of these interrelated brain mechanisms could be the focus of drug therapy.”

The study was published online in the Proceedings of the National Academy of Sciences. The research was conducted by Andres Buonanno, Ph.D., and his colleagues in the Section on Molecular Neurobiology in NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. Other authors of the paper were: Oh Bin Kwon, Daniel Paredes, Carmen M. Gonzalez, Joerg Neddens, and Detlef Vullhorst; all of the NICHD; and Luis Hernandez, of the Universidad de los Andes, Merida, Venezuela.

Schizophrenia affects about 1 percent of the U.S. population. Symptoms include delusions, hallucinations, disordered thinking and social withdrawal.

The finding ties together three previously separate bodies of research on the nature of schizophrenia, relating findings on the hereditary basis of the disorder to observations about how certain drugs affect the brain circuits.

Dr. Buonanno and his colleagues found that a molecule known as Neuregulin-1 starts a sequence of events in which a second molecule, dopamine, functions like a volume control knob to turn up or turn down the intensity of brain electrical activity correlated with long-term memory and related brain functions.

Cells called neurons make up the brain’s communications network, sending messages throughout the brain. Neurons end in long, cable-like projections. Vast networks of neurons are arrayed end to end, forming fibers that spread throughout the brain like telephone lines.

To send messages, neurons generate pulses of electricity. The pulses discharge certain brain chemicals from their cable-like projections. (Neuregulin-1 is one such chemical; dopamine is another.) These kinds of brain chemicals then bind to receptors on neighboring cells. The process is analogous to a key fitting into a lock. In an elaborate relay system, the neuron generates an electrical pulse, dislodging the chemical keys, which fit into the receptor locks on neighboring neurons. The process is repeated over and over again, transmitting messages on down the line.

In their study, Dr. Buonanno and his colleagues discovered that when Neuregulin-1 binds to its receptor (called ERB4) the receiving neurons release dopamine. Dopamine then binds to one or more of its receptors.

The binding of dopamine to its receptors controls the activity of another kind of brain chemical/receptor system. This system is known as the glutamatergic system and it is crucial to long-term memory and a number of other memory functions.

When these memory functions occur, the glutamatergic system becomes supercharged, in a process called long-term potentiation. The neurons generate stronger electrical pulses and make larger quantities of neurotransmitters and receptors.

In a series of experiments, the NIH researchers discovered that when dopamine binds to a type of receptor called the D4 receptor, long-term potentiation is reversed. The electrical activity in the glutamatergic cells slows down, and the cells make fewer neurotransmitters and receptors.

But turning down the electrical activity involved in long-term potentiation is only part of how dopamine influences the glutamatergic system, Dr. Buonanno explained. Other studies have shown that when dopamine binds to another receptor, called the D1 receptor, long-term potentiation is initiated, and formerly resting glutamatergic neurons increase their electrical activity and make more neurotransmitters and receptors.

“Dopamine appears to balance long-term potentiation, at times initiating it, and at other times, reversing it,” Dr. Buonanno said. “This implies that schizophrenia might involve an imbalance in the relationship between dopamine and long-term potentiation.”

Dr. Buonanno and his colleagues are now conducting research to determine whether dopamine regulates long-term potentiation directly, by acting on the glutamatergic neurons, or indirectly, by acting on another brain system that hasn’t yet been implicated in schizophrenia.

The study is the first to link Neuregulin-1 to the glutamatergic system by means of dopamine and its receptors.

Dr. Buonanno and his colleagues undertook the current study because of findings from other studies. In one body of research, scientists found many people with schizophrenia had variations in their genes for Neuregulin 1 and its receptor.

Still other studies had determined that the illicit drug PCP, which causes schizophrenia-like delusions and hallucinations, interferes with the neurotransmitters on glutamatergic neurons.

In the current study, Dr. Buonanno and his colleagues found that the drug clozapine, used to treat schizophrenia, blocks the D4 receptor, preventing dopamine from binding to it. The NIH researchers also discovered that using clozapine and other drugs to chemically block the D4 receptor, so that dopamine can’t bind to it, prevents Neuregulin-1 from reversing long-term potentiation.

Dr. Buonanno explained that theoretically, schizophrenia could result from a malfunction anywhere in the connections between the brain systems. This means that in addition to current drug treatments, which target the dopamine system, new schizophrenia treatments might target the Neuregulin system or the glutamatergic system.

Information on schizophrenia is available from NIH’s National Institute of Mental Health at


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