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Projects

Schizophrenia is a debilitating disease that is characterized by positive, negative, and cognitive symptoms. Understanding the cognitive symptoms in molecular terms is central for the study of schizophrenia because the degree of the cognitive symptoms is highly predictive of the long-term prognosis of the disease and these symptoms are resistant to treatment. Our main interest is therefore to understand the molecular mechanisms that may underlie the cognitive deficits of schizophrenia. Because schizophrenia has a strong developmental component we are particularly interested in how molecular and/or anatomical alterations during early brain development may affect cognition in the adult organism.

 

Striatal dopamine D2 receptor upregulation and cognition in the mouse:

To study the relationship between specific molecular alterations and cognition we are generating and analyzing genetically modified mice. In a first model we over-express dopamine D2 receptors selectively in the striatum to model the increased occupancy and density of striatal D2 receptors observed in patients with schizophrenia. However, rather than just upregulating these receptors in the striatum we use an artificial transactivator system that allowed us to temporally control the overexpression (Figure 1). We find that D2 receptor upregulation in the striatum induces behavioral deficits that are similar to the cognitive symptoms of patients with schizophrenia. Specifically, D2 transgenic mice show impairments in working memory tasks and conditioned associative learning, two cognitive processes that require the prefrontal cortex (Figure 2). In line with this, selective D2 receptor upregulation in the striatum alters dopamine turnover and D1 receptor activation in the prefrontal cortex, which may explain the behavioral deficits. Currently, we are studying the immediate effects of D2R upregulation on the electro-physiological properties of mediums spiny neurons in the striatum that may precede the alterations observed in the prefrontal cortex. We use patch clamp whole cell recordings for this purpose. In addition, we find that developmental upregulation of striatal D2 receptor is sufficient to induce prefrontal-dependent cognitive deficits, as these deficits persist in adulthood even when the transgene is turned off and D2R expression returns to normal levels. One hypothesis is that embryonic D2R upregulation in the striatum alters the connectivity of the brain. We are currently performing tracing studies in which we generate 3-dimensional reconstructions of axonal terminal fields in the cortico-striatal system .


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The thalamo-frontocortical projections and cognition in the mouse

Another focus in the lab is on studying the projections from the medio-dorsal thalamus to the prefrontal cortex that are thought to be altered in patients with schizophrenia. We are testing the hypothesis that a decrease in the thalamo-fronto-cortical projections causes cognitive symptoms and that activity of these neurons is required for cognitive processes that are dependent on the prefrontal cortex such as working memory. To this end, we use genetic tools to ablate or silence these projections in the mouse and study the behavioral consequences of these interventions. The genetic tools include the generation of transgenic mice and virally mediated gene expression. Using in vivo electrophysiological recordings we further study the neuronal mechanisms that are affected by the ablation and silencing experiments and therefore may be candidate mechanisms for mediating the cognitive deficits. These studies should guide the development of new medication against the cognitive deficits of schizophrenia.

Techniques that we use in the lab:

- Molecular techniques for the construction and analysis of genetically modified mice
- Stereotactic injections of dye tracers and adeno-associated viruses into the brain
- Behavioral analysis of genetically modified mice
- Tracing and three-dimensional reconstruction of dendritic and axonal arbor fields in the adult mouse
- Whole cell patch clamp recordings from fluorescently labeled neurons in brain slices
- Basic biochemical and histo-chemical analysis of genetically modified mice

 


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