Christoph Kellendonk

Christoph Kellendonk, Ph.D.

Assistant Professor, Psychiatry

630 West 168th Street, P&S Building 7-431
Tel +1 212 342-3114

Area of Research

Models of Psychiatric Disorders, Neurobiology of Learning and Memory, Neurogenetics


Dopamine signaling in the striatum; Behavioral analysis of genetically modified mice; How do alterations during brain development affect behavior in the adult animal


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.

To study the relationship between specific molecular alterations and cognition we are generating and analyzing genetically modified mice. In a first model we over-expressed 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 used an artificial transactivator system that allowed us to temporally control the overexpression. We found 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 showed impairments in working memory tasks and conditioned associative learning, two cognitive processes that require the prefrontal cortex. 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.

In addition, we found 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. In the future, a major focus of the laboratory will be to address what are the physiological and possible morphological alterations induced by developmental D2 receptor upregulation that ultimately lead to the behavioral deficit in the adult animal.

We believe that the findings obtained with the D2 transgenic mice will be very informative for research in schizophrenia because they suggest that striatal D2 receptors may be more important for the genesis of cognitive symptoms than it has generally been assumed. In addition, because the effects occur during development, they suggest that antipsychotic medication, which is mainly directed against D2 receptors, may not improve cognitive symptoms because they are given to late, after compensation has occurred.