In a study published in Proceedings of the National Academy of Sciencesresearchers from Case Western Reserve University School of Medicine have uncovered a novel mechanism in which a protein — neuregulin 3 (NRG3) — controls how key neurotransmitters are released in the brain during schizophrenia. The current study is the first to investigate how protein causes such severe mental illness.

In the study, the scientists used genetic, electrophysiological, biochemical, and molecular techniques to uncover the function of NRG3. They discovered it suppresses a protein complex required for proper neuron communication. Certain variations in the gene encoding NRG3 are considered risk factors for schizophrenia.

"We have identified a novel function of a schizophrenia susceptibility gene, neuregulin 3, which provides insight into cellular mechanisms of this devastating disorder and could lead to new therapeutic targets," said senior author Lin Mei, professor and chair of the department of neurosciences at Case Western Reserve University School of Medicine.

Schizophrenia affects nearly 1 in 100 American adults and is poorly understood, says Mei. It is difficult to tease apart the many interrelated proteins and neurotransmitters behind the disease. Mei's study outlines a previously unknown mechanism found in neurons affected by schizophrenia.

In the new study, researchers mutated the gene encoding NRG3 in mice — but only in certain populations of neurons. When they mutated NRG3 in neurons that help activate the brain — called pyramidal neurons — the genetically modified mice displayed behavior consistent with schizophrenia.

They had healthy hearing and reflexes, but were unusually active. They had trouble remembering and navigating mazes. In social interactions, the mice shied away from strangers. The experiments not only supported a role for NRG3 in schizophrenia but also helped define types of neurons involved.

By studying brain samples from the mice, the researchers learned how NRG3 works at the cellular level. They found it inhibits assembly of a complex of proteins at synapses, the place where adjacent nerve cells communicate. Neurons need the complex, called SNARE, to transmit certain neurotransmitters between each other.

In particular, SNARE complex helps neurons transmit glutamate — the most common "excitatory" neurotransmitter in the brain. Glutamate helps activate neurons and is essential for learning. Glutamate imbalances can cause schizophrenic symptoms.

People with severe mental illnesses like schizophrenia, bipolar disorder, and major depression, tend to have higher levels of NRG3. The researchers mimicked protein levels found in the brains of schizophrenics by elevating NRG3 in cultured neurons, and found higher levels of NRG3 suppresses glutamate release.

Cells with high levels of NRG3 couldn't form SNARE complexes properly. Too much of the inhibitory protein prevented the complex from forming, and suppressed glutamate levels in the brain cells. The researchers concluded that NRG3 is critical to proper glutamate transmission in the brain.

The findings suggest NRG3 could serve as a new therapeutic target to help treat schizophrenia or other mental illnesses. Drugs that target NRG3 could help restore glutamate levels in certain types of neurons — a novel approach to schizophrenia treatment.

"Identifying a novel mechanism of action is a prerequisite to understanding a disorder, and to development of therapeutic interventions," Mei said. "Of course, the road could be long to get there, but we are on our way."