In a new study, Buffalo University geneticists have demonstrated how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.
The scientists have tested the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.
“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” explained Prof Michal Stachowiak of the University at Buffalo’s School of Medicine and Biomedical Sciences, lead author of a paper published in the journal Schizophrenia Research.
The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder.
“A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes,” Prof Stachowiak said. “How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?”
“It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.
“INFS functions like the conductor of an orchestra. It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”
Using embryonic stem cells, Prof Stachowiak’s team found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.
“We believe that FGFR1 is the conductor that physically interacts with all genes that affect schizophrenia. We think that schizophrenia occurs when there is a malfunction in the transition from stem cell to neuron, particularly with dopamine neurons.”
The scientists tested their hypothesis by creating an FGFR1 mutation in mice, which produced the hallmarks of the human disease: altered brain anatomy, behavioral impacts and overloaded sensory processes. “By attacking the INFS pathway, we were able to produce schizophrenia in mice,” Prof Stachowiak said.
“If such a generalized genomic pathway is causing the disease, then it should be possible to treat the disease with a more generalized approach. We may even be able to devise ways to arrest development of the disease before it presents fully in adolescence or adulthood.”
Bibliographic information: M.K. Stachowiak et al. Schizophrenia: A neurodevelopmental disorder — Integrative genomic hypothesis and therapeutic implications from a transgenic mouse model. Schizophrenia Research, vol. 143, no. 2–3, pp. 367–376; doi: 10.1016/j.schres.2012.11.004