Summary: Scientists reduced schizophrenia-like symptoms in mice by restoring the ErbB4 receptor in adulthood.
Source: Case Western Reserve University.
Schizophrenia remains a poorly understood brain disorder despite decades of research. One promising line of investigation focuses on receptors at the surfaces of brain cells that respond to growth factors. Many prior animal studies disrupted these receptors during early development in mice, yet schizophrenia typically emerges in adulthood. This raised a key question: do schizophrenia-like deficits in animal models arise from altered brain development, or from impaired cellular communication that develops later?
In a study published in the Proceedings of the National Academy of Sciences, Lin Mei, MD, PhD, and colleagues set out to resolve whether receptor alterations must occur early to produce lasting symptoms, or whether correcting receptor function in adults can reverse deficits. Mei, professor and chair of neurosciences at Case Western Reserve University School of Medicine, led an international team including Wen-Cheng Xiong, PhD, and first authors Hongsheng Wang and Wenbing Chen, along with collaborators from institutions in China and the Medical College of Georgia at Augusta University.
The team focused on the ErbB4 receptor, which is altered in adults with schizophrenia. ErbB4 interacts with the neurotrophic factor NRG1 and plays a crucial role in maintaining GABAergic signaling. GABA is the primary inhibitory neurotransmitter in the brain; it prevents excessive neuronal firing and helps regulate fear and anxiety. Previous work showed that ErbB4 mutations can alter intracellular signaling and produce behavioral changes reminiscent of schizophrenia in mice, but it remained unclear whether these effects reflect developmental wiring defects or adult-phase communication failures.
To address this, the researchers created two complementary mouse models with temporal control over ErbB4 expression. In the first model, they used an inducible genetic system to switch off ErbB4 only after mice reached adulthood. These adult-specific knock-out mice showed impaired behavior and reduced GABA release, yet their neuronal numbers and morphology appeared normal. This result indicates that disrupting ErbB4 signaling in adulthood is sufficient to produce behavioral deficits, independent of early developmental brain wiring.
In the second model, ErbB4 was absent throughout development, producing malformed circuits and fewer interneurons. The researchers then reactivated ErbB4 expression in adulthood—effectively rescuing receptor function on circuits that developed without it. Remarkably, restoring ErbB4 in adult animals improved performance on behavioral tests: hyperactivity diminished and fear responses moved toward normal ranges. These improvements occurred even though aspects of circuit anatomy established during development remained altered.
Together, findings from the two models indicate that ErbB4 has a critical role in adult GABAergic transmission and behavior. Deficits observed in adult animals can arise from impaired receptor signaling during adulthood, and conversely, reinstating ErbB4 signaling in adults can partially reverse behavioral abnormalities even when developmental wiring is imperfect.
“When ErbB4 is mutated early on in mice, it impairs circuit wiring and GABA transmission in adults, causing schizophrenia-like symptoms,” Mei explained. “Our new experiments show that adult-stage communication deficits contribute substantially to those symptoms, and that restoring ErbB4 in adulthood can alleviate them.”
The study highlights a nuanced therapeutic implication: some interventions might not need to reverse developmental wiring to yield clinical benefit. Instead, therapies that restore or enhance ErbB4-related signaling and normalize GABAergic regulation in the adult brain could improve symptoms in patients where ErbB4 function is compromised.
Mei and colleagues report that restoring ErbB4 reduced hyperactivity and normalized fear responses in adult mice, suggesting that correcting ErbB4 signaling may be a viable strategy for certain forms of psychiatric illness. The team is now investigating the cellular mechanisms by which adult restoration of ErbB4 improves neurotransmitter signaling and whether similar approaches could affect other psychiatric conditions, such as attention deficit hyperactivity disorder and major depression.
Funding: This research was supported in part by grants from the National Institutes of Health (MH083317, MH109280, NS082007, NS090083 to L.M.; AG051773 and AG045781 to W-C.X.).
Source: Ansley Gogol, Case Western Reserve University
Publisher: Organized by NeuroscienceNews.com
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: 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. Article: “Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice,” Proceedings of the National Academy of Sciences. Published November 29, 2018.
doi: 10.1073/pnas.1811287115
Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice
The neurotrophic factor NRG1 and its receptor ErbB4 contribute to the assembly and function of GABAergic circuits during development and in the mature brain. ErbB4 null mice show reduced interneuron numbers, diminished GABA release, and behavioral impairments. Using two mouse strains with temporal control over ErbB4 deletion and expression, the authors demonstrate that deleting ErbB4 in adulthood impairs behavior and GABA release without altering neuron numbers or morphology. Conversely, restoring ErbB4 in adult null mice alleviates some functional deficits despite developmental abnormalities. These results indicate that NRG1–ErbB4 signaling plays a crucial role in adult GABAergic transmission and behavior and suggest that postdevelopmental restoration of this pathway might benefit relevant brain disorders.