Effect of Genotype on Brain Function and Structure in Schizophrenia

Lay Summary

Are Functional and Structural Brain Deficits in People with Schizophrenia Related to a Specific Gene?

Colorado researchers will combine MRI imaging with genetic studies to explore the possibility that structural and functional brain deficits in people with schizophrenia are associated with a specific gene.  If so, the research could identify new a new genetic target for drug therapy.

One of the most common problems for people with schizophrenia is the inability to filter out unimportant sounds (called “sensory gating deficit”).  Studying schizophrenic patients with MRI imaging, the researchers found increased brain activity in the thalamus and hippocampus, suggesting that these regions may fail to block sensory overload. Additionally, they found that patients’ cells in these two brain regions had far fewer “α7 nicotinic receptors” than expected. These receptors, located on cells, are activated by the neurotransmitter acetylcholine for cell to cell communication and are also activated by nicotine (which has been found in some studies to temporarily alleviate the sensory overload). The gene that produces this receptor has been identified, and small variations in the gene result in production of fewer α7 nicotinic receptors.

The researchers hypothesize that people with schizophrenia have variations in this gene, resulting in poor sensory inhibition by brain cells in the thalamus and hippocampus and in structural differences in the brain’s gray and white matter in these two regions. They will test this hypothesis by comparing imaging results in patients and healthy “control” participants.  The investigators will use fMRI to see whether patients have increased sensory input in the thalamus and hippocampus, compared to controls; and, “voxel-based morphometry” will be used to compare white and gray matter volumes in these brain areas in patients and controls. If gene variations are implicated, drugs that are under development to act on this receptor could be tested for their ability to restore function in the hippocampus and thalamus to normal levels.

Significance:  The findings may lead to development of new treatments that improve the ability of people with schizophrenia to block out unimportant sounds and to focus attention.  This improvement, in turn, could increase their capacity to interact in their environment and improve their cognitive skills.

Abstract

Effect of Genotype on Brain Function and Structure in Schizophrenia

Schizophrenia is a complex neurobiological disorder resulting from the interaction of multiple genes and environmental factors. One gene that may be involved in the pathology of schizophrenia is the α7 nicotinic receptor gene, which has been linked both to schizophrenia itself, and to an elementary deficit in sensory processing observed in schizophrenia patients and their relatives. A key missing link in understanding how genotype relates to disease pathology is knowing how alterations in the gene lead to changes in brain function and structure. To address this question, the proposed study will evaluate brain function and structure in the context of genetic information in subjects with schizophrenia and healthy controls.

Aim #1 will determine the effects of polymorphisms in the α7 nicotinic receptor gene on brain hemodynamic response during auditory sensory gating in individuals with schizophrenia and healthy comparison subjects. Inhibitory deficits in sensory gating are one of the most reproducible physiological deficits associated with schizophrenia, and have recently been successfully imaged in our laboratory with fMRI. We will test the hypothesis that increased hemodynamic response (consistent with diminished inhibition) will be observed in subjects with polymorphisms in the α7 nicotinic receptor gene, regardless of diagnosis.

Aim #2 will use voxel-based morphometry to determine the effects of the polymorphisms on brain structure, including gray and white matter volume. This aim will test the hypothesis that subjects with polymorphisms in the α7 nicotinic receptor gene will have decreased volume (consistent with neuronal and glial developmental abnormalities) in brain regions where the gene is maximally expressed (e.g. hippocampus and thalamus). This would be one of the first studies to examine genetic effects on both functional and structural measures as assessed by MRI.