PNAS paper describes microscopic changes that support the role of glutamatergic neurons in disease development.

Disrupting the function of a key cranial molecule leads to microscopic brain abnormalities and schizophrenia in mice, according to a team from The Scripps Research Institute. Neuregulin is an important developmental protein that helps the brain form its distinct structures early in development.

They also found that the schizophrenic mice could recover normal behavior when treated with clozapine, a decades-old drug sometimes used to treat schizophrenia in people. They thus suggest that these mice might provide researchers with a good model for studying the disease. This study also provides support for the schizophrenia hypothesis that implicates glutamatergic neurons, because the mice had problems with their glutamatergic synapses.

The abnormalities found the mouse brains were similar to those seen in the autopsied brains of people who were diagnosed with schizophrenia, the scientists note. Also, genetic studies have linked inherited forms of this protein and its receptors to schizophrenia and numerous other mental health problems, they add.

In the study, the team effectively removed the function of neuregulin by eliminating the receptor to which it binds. Because this is such an important developmental protein, they expected that eliminating its receptor would severely impact the development of the mouse’s brain. As it turns out, the brains were normal overall, but the loss of neuregulin did affect the brain on a microscopic level. 

Investigators revealed that when mice are deprived of neuregulin, their dendritic spines start to form but do not completely mature. Instead they fall apart while the brain itself matures.  The effect of this loss is evident in behavior tests, where mice display hallmarks of schizophrenia, such as social interaction problems and reduced anxiety.

Loss of the spines also kept mice from adapting to and anticipating a startling noise, which is a classic sign of a schizophrenia-like state, the Scripps team explains.

The findings were published this week in the early edition of the journal Proceedings of the National Academy of Sciences.


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