Developmental biology - Brain Development|
Alleviating Schizophrenia In Mice
Restoring brain cell receptors helps restore normal behavior...
Despite extensive research, schizophrenia remains one of the least understood brain disorders. Although there is one promising area, the receptors on brain cell surfaces — receptors that identify growth factors. But, previous schizophrenia studies focused on brain cell receptors of very young mice, while schizophrenia usually affects adults.
In a recent issue of the Proceedings of the National Academy of Sciences (PNAS), research conducted by Lin Mei MD PhD, wanted to find if all tinkering in young mice hampered their brain development, causing schizophrenia-like symptoms - or, did their brain cells develop normally, but in adulthood begin struggling to communicate? Researchers needed to know whether to focus their efforts on (1) brain cell development or (2) communication, or (3) both. The answer implies different therapeutic approaches.
In the new study, Mei, professor and chair of neurosciences at Case Western Reserve University (CWRU) School of Medicine, led an international team of neuroscientists from CWRU, researchers at Nanchang University and Guangzhou Medical University in China, and neuroscientists from the Medical College of Georgia at Augusta University.
Together, they studied a brain cell receptor — ErbB4 — the level of which is altered in adults with schizophrenia. ErbB4 helps inhibit the brain neurotransmitter — GABA — which prevents brain cells from overreacting to fear and/or anxiety. They previously had revealed that ErbB4 mutations change signals inside of brain cells which presents as schizophrenic symptoms in mice.
"When ErbB4 is mutated early in mouse development, it impairs brain circuit wiring. It also impairs GABA transmission in adults causing schizophrenic symptoms. But past mouse models were unable to distinguish between deficits from abnormal development in young mouse brains, or abnormal transmission developed later in life."
Lin Mei MD PhD, Department of Neurosciences, School of Medicine, Case Western Reserve University and Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
New study results show schizophrenic symptoms arise with deficits in how brain cells communicate during adulthood, regardless of whether or not they became fully developed. To find answers, Mei's team genetically engineered two new mouse models of schizophrenia:
• In the first, researchers treated mice with a chemical to turn 'off' the gene for ErbB4. Results showed that in adult mice missing ErbB4, brain cell development and outward appearance seem normal, but symptoms persist. The experiment suggested schizophrenic symptoms in adult mice were unrelated to abnormal brain cell development.
• In the second mouse model, the brain cell receptor was missing in mice from the beginning, hampering brain cell development. Researchers used the same genetic switch to turn ErbB4 'on' in adulthood — in essence, recovering its function.
Mei: "In recovered knock-out mice, ErbB4 is missing during development and mice have crippled brain circuits. Yet, when ErbB4 is restored on a malformed circuit, mice score better in behavioral tests."
Even with underdeveloped brain cells, schizophrenic symptoms were alleviated simply by adding ErbB4. Restoring ErbB4 receptors reduced hyperactivity, and normalized fear responses in adult mice.
This study shows correcting ErbB4 signaling could be therapeutic in relevant patients, confirming that ErbB4 is critical to how brain cells communicate during adulthood. The nuanced distinction could lead to new therapeutics designed to improve brain cell signaling associated with the ErbB4 receptor. In particular, therapeutics that improve how GABA neurotransmitters regulate brain cell activity.
"Restoring ErbB4 could be beneficial to patients — even those with malformed brain circuitry. 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 and major depression."
Lin Mei MD PhD
NRG1–ErbB4 signaling is implicated in GABAergic circuit assembly during development and GABAergic transmission at adulthood. However, it is unclear whether phenotypes in the adult stage in ErbB4 mutant mice result from abnormal neural development. By using two strains of mice with temporal control of ErbB4 deletion and expression, we demonstrate that ErbB4 deletion in adult mice impaired behavior and GABA release, whereas deficits due to ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate that NRG1–ErbB4 signaling at adulthood is critical to GABAergic transmission and behavior and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.
Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1–ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. 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.
Hongsheng Wang, Fang Liu, Wenbing Chen, Xiangdong Sun, Wanpeng Cui, Zhaoqi Dong, Kai Zhao, Hongsheng Zhang, Haiwen Li, Guanglin Xing, Erkang Fei, Bing-Xing Pan, Bao-Ming Li, Wen-Cheng Xiong and Lin Mei.
This research was supported in part by grants from the National Institutes of Health (MH083317, MH109280, NS082007, and NS090083 to L.M.; and AG051773 and AG051773 and AG045781 to W-C.X.)
For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
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Dec 5, 2018 Fetal Timeline Maternal Timeline News News Archive
Research found restoring ErbB4 receptors reduced hyperactivity, and normalized fear responses
in adult mice with abnormal neural development. Image fabricated with mouse brain.