About 1% of the world’s population is affected by schizophrenia (SZ), a type of mental disorder that changes basic brain processes of perception, emotion, and judgment, but which is also one of the least understood of the brain disorders. Scientists at Case Western Reserve University and colleagues in the U.S. and China have now shown how restoring levels of one brain receptor, ErbB4, can help to reduce the symptoms of schizophrenia in the brains of adult knockout mice. Their results indicate that ErbB4 could also represent a target for human therapeutics.

“Restoring ErbB4 could be beneficial to patients—even those with malformed brain circuitry,” said Lin Mei, M.D., Ph.D., professor and chair of neurosciences at Case Western Reserve University School of Medicine. “We are now looking into how restoring ErbB4 improves neurotransmitter signaling inside brain cells, including those relevant to other psychiatric disorders, such as attention deficit hyperactivity disorder and major depression.”

The team reported its findings in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice.”

Signaling by neurotrophic factor neuregulin 1 (NRG1) and its receptor tyrosine kinase ErbB4 plays a key role in neuronal development. ErbB4 is involved in maintaining the inhibitory neurotransmitter GABA. Both human and rodent studies have linked changes to NRG1 and ErbB4 and their genes with schizophrenia, and mouse studies by Dr. Mei’s team indicated that ErbB4 mutations alter neuronal signaling in the brain, which leads to symptoms of schizophrenia. “When ErbB4 is mutated early on in mice, it impairs brain circuit wiring,” Dr. Mei commented. “It also impairs GABA transmission in adult animals, causing schizophrenic symptoms.”

Investigating the role of NRG1-ErbB4 signaling in rodent models hasn’t led to any definitive answers about whether the disorder develops due to abnormal brain cell development or due to abnormal neuronal communication because genetic manipulation to generate ErbB4 mutations is carried out in very young mice, whereas schizophrenia tends to develop in adults. “… previous models are unable to distinguish whether deficits are from abnormal development in young mice brains, or abnormal transmission developed later on,” Dr. Mei added.

To try and answer this question the Case Western Reserve University team, working with colleagues at Nanchung University and Guangzhou Medical University in China, and the Medical College of Georgia at Augusta University, developed two new mouse models of schizophrenia. In one inducible knockout model, the ErbB4 gene could be chemically, but reversibly, switched off in adult mice. In the second, recovery knockout mouse model ErbB4 was absent from early development, but could be restored later in life.

In these inducible knockout animals, early brain cell development and appearance were normal, but the mice demonstrated symptoms of schizophrenia after ErbB4 was knocked out during adulthood.”Using inducible knock-out mice we depleted ErbB4 only in adult animals, and showed that this impairs behavior,” said Dr. Mei. “We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology,” the authors wrote.

In contrast with normal brain development seen in the inducible knockout animals, neuronal circuitry was impaired in the recovery knockout animals in which ErbB4 was switched off during early development. These mice also displayed symptoms of schizophrenia. However, some of the symptoms of schizophrenia could be reduced when ErbB4 was restored during adulthood. “… some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage,” the authors stated.

“In recovery knock-out mice, ErbB4 is missing during development and thus the mice have crippled brain circuits,” added Dr. Mei. “Yet, when ErbB4 is restored on a malformed circuit, mice scored better in behavioral tests … This study shows correcting ErbB4 signaling could be therapeutic in relevant patients.”

“Together, our results indicate a critical role of NRG1–ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders,” the researchers concluded. “These results provide compelling evidence that ErbB4 is critical for synaptic transmission and plasticity after development and suggest that restoring ErbB4 signaling could be beneficial to relevant SZ.”

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