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.
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
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