Genetic Scientists Eliminate Schizophrenia Symptoms in Mice

A multinational group of geneticists writing in the journal Neuron has reversed schizophrenia-like symptoms in adult mice by restoring normal expression to a gene called Neuregulin-1 (NRG1 for short).

Roles of Neuregulin 1 in neural development. NRG1 is released from neurons to promote the formation and maintenance of radial glial cells. Tangential migration of γ-aminobutyric acid-ergic interneurons requires NRG1 in the cortical region. Myelination and ensheathment of peripheral nerves are controlled by the amounts of NRG1 produced in substrate axons. NRG1 from axons might regulate oligodendrocyte development and myelination of axons in the CNS. NRG1 is also necessary for the formation of neuromuscular junctions - NMJs. NRG1 stimulates CNS synapse formation (Lin Mei & Wen-Cheng Xiong, 2008)

Roles of Neuregulin 1 in neural development. NRG1 is released from neurons to promote the formation and maintenance of radial glial cells. Tangential migration of γ-aminobutyric acid-ergic interneurons requires NRG1 in the cortical region. Myelination and ensheathment of peripheral nerves are controlled by the amounts of NRG1 produced in substrate axons. NRG1 from axons might regulate oligodendrocyte development and myelination of axons in the CNS. NRG1 is also necessary for the formation of neuromuscular junctions – NMJs. NRG1 stimulates CNS synapse formation (Lin Mei & Wen-Cheng Xiong, 2008)

Targeting expression of NRG1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder.

Like patients with schizophrenia, adult mice biogenetically-engineered to have higher NRG1 levels showed reduced activity of the brain messenger chemicals glutamate and γ-aminobutyric acid (GABA). The mice also showed behaviors related to aspects of the human illness.

“They genetically engineered mice so they could turn up levels of NRG1 to mimic high levels found in some patients then return levels to normal,” explained senior author Dr Lin Mei from the Medical College of Georgia at Georgia Regents University.

“They found that when elevated, mice were hyperactive, couldn’t remember what they had just learned and couldn’t ignore distracting background or white noise. When they returned NRG1levels to normal in adult mice, the schizophrenia-like symptoms went away.”

While schizophrenia is generally considered a developmental disease that surfaces in early adulthood, the team found that even when they kept NRG1 levels normal until adulthood, mice still exhibited schizophrenia-like symptoms once higher levels were expressed. Without intervention, they developed symptoms at about the same age humans do.

“This shows that high levels of NRG1 are a cause of schizophrenia, at least in mice, because when you turn them down, the behavior deficit disappears,” Dr Mei said. “Our data certainly suggests that we can treat this cause by bringing down excessive levels of NRG1 or blocking its pathologic effects.”

“Schizophrenia is a spectrum disorder with multiple causes – most of which are unknown – that tends to run in families, and high NRG1 levels have been found in only a minority of patients. To reduce NRG1 levels in those individuals likely would require development of small molecules that could, for example, block the gene’s signaling pathways,” Dr Mei said.

“Current therapies treat symptoms and generally focus on reducing the activity of two neurotransmitters since the bottom line is excessive communication between neurons.”

The good news is it’s relatively easy to measure NRG1 since blood levels appear to correlate well with brain levels. To genetically alter the mice, the scientists put a copy of the NRG1 gene into mouse DNA then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining the teeth of fetuses and babies. The mice are born expressing high levels of NRG1 and giving the antibiotic restores normal levels.

“If you don’t feed the mice tetracycline, the NRG1 levels are always high. Endogenous levels of the gene are not affected. High-levels of NRG1 appear to activate the kinase LIMK1, impairing release of the neurotransmitter glutamate and normal behavior. The LIMK1 connection identifies another target for intervention,” Dr Mei concluded.

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Bibliographic information: Dong-Min Yin et al. 2013. Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1. Neuron, vol. 78, no. 4, pp. 644-657; doi: 10.1016/j.neuron.2013.03.028