New Mouse Model of Schizophrenia Links Structure, Function Deficits

By Lois Baker

Release Date: October 5, 2006 This content is archived.


BUFFALO, N.Y. -- Schizophrenia researchers historically have aligned themselves into two opposing camps: structuralists and functionalists.

Structuralists have pursued the idea that the brains of schizophrenics show structural changes in the cortex and brain stem. Functionalists have held to the dopamine antagonist theory: that the neurotransmitter dopamine is malfunctioning, causing the disease's characteristic delusions and hallucinations.

"These two camps don't talk to one another," said Michal Stachowiak, Ph.D., neuroscientist and senior researcher on a University at Buffalo team that appears to have broken that stalemate.

He and Ewa K. Stachowiak, Ph.D., created a transgenic mouse missing a critical brain component called the fibroblast growth factor receptor. The mouse displays the structural and neurochemical changes in dopamine neurons similar to those seen in PET scans of human patients with schizophrenia.

"Our new model has the potential to allow, for the first time, a way to search for new therapeutic treatments that target brain development or compensate for the abnormal structure of dopamine producing neurons," said Stachowiak,

"It provides a new unifying concept of schizophrenia as a neuroanatomical-biochemical disorder.

"The mice display characteristic behavioral symptoms, such as an impaired processing of sensory information, which was reversed by a dopamine receptor antagonist used to treat schizophrenia," said Stachowiak. "In other animal models, behavioral symptoms were induced by manipulating dopamine transmission only, without the underlying structural changes in the dopaminergic neurons.

Results of the research were published in a recent issue of the Journal of Neurochemistry.

The two known conditions inherent in schizophrenics -- underdeveloped dopamine-producing regions in their brains, but too much dopamine in their systems -- seemed to contradict each other, said Stachowiak.

The crux of the research was proving that the two conditions were interconnected. The investigators found that both the dopamine-producing regions in the brain and the new cells within those regions were smaller than normal, prompting the neurons to overcompensate and overproduce dopamine.

Consequently, treating schizophrenics with drugs that block dopamine's action only dampens this function, but doesn't control it, Stachowiak said.

Stachowiak is professor of pathological and anatomical sciences and chemistry and director of the Molecular and Structural Neurobiology and Gene Therapy Program at UB. Ewa Stachowiak is UB research instructor in pathology and anatomical sciences and chemistry. Ilona Klejbor, a post-doctoral researcher in Stachowiak's laboratory, now at the Medical University of Gdansk, in Gdansk, Poland, is first author on the paper.

The neurobiology team, along with Robert Miletich, M.D., UB clinical associate professor of nuclear medicine, currently is searching for a "fingerprint" that identifies those at risk of developing the disease by looking for common brain symptoms in schizophrenic patients and the animal model.

If such a risk factor could be found, said Stachowiak, children with behavioral problems or from families with a history of schizophrenia could be screened, and treatment could be started before the disease becomes full-blown.

Additional authors on the paper are Jason M. Meyers, graduate student; Thomas D. Corso, Ph.D., visiting professor, and Robert Hard, Ph.D., professor, all from the UB Department of Pathology and Anatomical Sciences; Jerry Richards, Ph.D., and Kathy Hausknecht, student researcher, both from the UB Research Institute on Addictions; Angelo S. Gambino, a student researcher from Canisius College in Buffalo; Janusz Morys, Ph.D., from the Medical University of Gdansk, and Pamela A. Maher, Ph.D., from the Salk Institute in La Jolla, Calif.

The research was funded by grants from the March of Dimes and Birth Defects, the John R. Oishei Foundation, the Canisius College Learning Excellence Program and the National Institutes of Health.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The university is in full compliance with mandates of state and federal regulatory agencies pertaining to the humane use and care of research animals.