Michal Stachowiak, PhD.

Michal Stachowiak and colleagues have developed a new mouse model of schizophrenia that shows how gestational brain changes may cause behavioral problems later in life.

UB Scientists Offer First Genomic Explanation for Schizophrenia

Published February 11, 2013

New UB research shows how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.

“We believe this is the first model that explains schizophrenia from genes to development to brain structure and, finally, to behavior.”
Michal Stachowiak, PhD
professor of pathology and anatomical sciences

The study, published in Schizophrenia Research, points toward a broad-based approach to treating, or perhaps even preventing, the disorder.

Gene Mutation Leads to Systemic Malfunction

The UB study explains how numerous genetic mutations can result in schizophrenia.

The researchers produced the disorder in mice by attacking a genomic pathway known as Integrative Nuclear FGFR 1 Signaling, or INFS.

A system that controls the development of the entire brain, the INFS serves as a central intersection point for multiple pathways of as many as 160 different genes implicated in schizophrenia.

The researchers hypothesize that the disorder develops when an alteration or mutation in a single schizophrenia-linked gene leads to a cascading effect, causing the INFS system to malfunction.

“We think that schizophrenia occurs when there is a malfunction in the transition from stem cell to neuron, particularly with dopamine neurons, says lead author Michal Stachowiak, PhD, professor of pathology and anatomical sciences.

The INFS pathway is key in this process because it integrates diverse neurological signals that control the development of embryonic stem cells and neural progenitor cells, he adds.

From Genes to Behavior, a Disorder Explained

Stachowiak and his colleagues tested their hypothesis with embryonic stem cells. They found that some of the genes implicated in schizophrenia bind the fibroblast growth factor receptor protein. Significantly, this protein, FGFR1, is believed to interact with all genes that affect schizophrenia, says Stachowiak.

When the researchers created an FGFR1 mutation in mice, the animals had the hallmarks of the human disease: altered brain anatomy, behavioral impacts and overloaded sensory processes.

“We believe this is the first model that explains schizophrenia from genes to development to brain structure and, finally, to behavior,” says Stachowiak, who directs the Stem Cell Engraftment and In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center (WNYSTEM).

Toward Broad-based Treatment, Prevention

If a generalized genomic pathway causes the disease, it should be possible to treat it with a more generalized approach, Stachowiak says.

“We may even be able to devise ways to arrest development of the disease before it presents fully in adolescence or adulthood,” he notes.

The UB research adds to existing evidence that nicotinic agonists, often prescribed as smoking cessation drugs, could help improve cognitive function in people with schizophrenia by acting on the INFS.

Long believed to be a form of self-medication, smoking is seen at much higher rates in people with schizophrenia than in the general population.

Multiple Funders, Collaborators

The study was funded by New York State Stem Cell Science (NYSTEM), UB and the March of Dimes.

The multidisciplinary research team included UB co-authors from the Department of Pathology and Anatomical Sciences:

  • B. Birkaya, PhD, and E. K. Stachowiak, PhD, both research assistant professors;
  • S. Narla, D. Prokop, C. Syposs, C. Terranova, A. Kucinski and R. Curl, all graduate students

from the Department of Psychology:

  • S. Wersinger, PhD, assistant professor
  • Y. Yang, undergraduate

from the Department of Chemical and Biological Engineering and WNYSTEM:

  • A. Parikh, doctoral candidate
  • E.S. Tzanakakis, PhD, associate professor

Additional coauthors are:

  • I. Klejbor of Gdansk Medical University
  • M. Bencherif of Targacept Inc.
  • T. Corso of Lake Erie College of Osteopathic Medicine