F A C U L T Y P R O F I L E
KELLENDONK, CHRISTOPH, PH.D.
Molecular mechanisms that may underlie the cognitive deficits of schizophrenia.
Office: Physicians & Surgeons | 7th Floor | Room 421
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 for 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.
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. To obtain temporal control of transgene expression we used an artificial transactivator system that allowed us to switch off the transgene in the adult animal. We found that D2R upregulation in the striatum leads to cognitive deficits in prefrontal-dependent tasks that are reminiscent to cognitive deficits in schizophrenia. Moreover, D2R-OE mice show deficits in incentive motivation paralleling the negative symptoms of the disease. Interestingly, the motivational deficits are reversed upon switching off the transgene while the cognitive impairments persist, suggesting different underlying mechanisms. Currently we are identifying the physiological and molecular mechanisms that are responsible for the deficits in cognition and motivation.
Another focus in the lab is on studying the function of the medio-dorsal thalamus in cognition. Morphological studies have shown that the projections from the medio-dorsal thalamus to the prefrontal cortex are altered in patients with schizophrenia. However, it is unclear whether this has any functional implication with regard to cognition. We hypothesis that activity of medio-dorsal neurons is required for prefrontal dependent cognition and that a decrease in the thalamo-fronto-cortical projections - as observed in schizophrenia - will causes cognitive deficits. To test this hypothesis, we study in a second model the behavioral consequences of ablating and silencing these projections in the mouse.
1. C. Kellendonk, E. Simpson, H.J. Polan, G. Malleret, S. Vronskaya, V. Winiger, H. Moore, E.R. Kandel (2006) Transient and Selective Over-Expression of Dopamine D2 Receptors in the Striatum Causes Persistent Abnormalities in the Prefrontal Cortex. Neuron 49, 603-615
2. M. Drew, E.H. Simpson, C. Kellendonk, G. Herzberg, O. Olipatov, S. Fairhurst, E.R. Kandel, C. Malapani, P. Balsam (2007) Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing J. Neuroscience 27:7731-9
3. M.E.Bach, E.S. Simpson, L. Kahn, J. Marshall, E.R. Kandel, C. Kellendonk (2008) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent deficits in conditioned associative learning Proc Natl Acad Sci U S A 105:16027-324.
4. C. Kellendonk, E.H. Simpson, E.R. Kandel (2009) Modeling Schizophrenia Endophenotypes in Mice Trends in Neuroscience 32:347-358
5. C. Kellendonk (2009) Modeling excess striatal D2 receptors in mice. Prog Brain Res 159:59-65
6. E.H. Simpson, C. Kellendonk, E.R. Kandel (2010) A possible role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia. Neuron 65(5):585-596
7. A.M. Miller, R. Bansal, X. Hao, J. P. Sanchez-Pena, L.J. Miller, J. Liu, D. Xu, H. Zhu, M.M. Chakravarty, K. Durkin, I. Ivanov, K.J. Plessen, C. Kellendonk, B.S. Peterson (2010) Enlargement of thalamic motor nuclei in persons with Tourette Syndrome. Archives of General Psychiatry 67(9):955-64
8. E.H. Simpson*, C. Kellendonk*, R.D. Ward, V. Richards, O. Lipatova, S. Fairhurst, E.R. Kandel, P.D. Balsam (2011) Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of Schizophrenia. Biol. Psychiatry 69:928-35 | * Both authors contributed equally to this work
9. M. Cazorla, J. Prémont, A. Mann, N. Girard, C. Kellendonk, D. Rognan (2011) Virtual screening identifies a low-molecular weight TrkB antagonist with anxiolytic and antidepressant potential in mice Journal of Clinical Investigation 121:1846-57