My laboratory uses mouse genetic tools in an effort to understand the biology that underlies the symptoms of schizophrenia. Schizophrenia is characterized by three symptom clusters: the so-called cognitive, negative and positive symptoms. While the positive symptoms – which include disordered thought processes, hallucinations and delusions – are the most characteristic feature of the disorder, such symptoms are more difficult to model in the mouse. In contrast, the cognitive and negative symptoms of the disorder – including deficits in working memory and motivation – have behavioral readouts homologous to humans in mouse models. Such mouse models are therefore very useful to study the biological underpinnings of deficits in these behaviors. This is important because cognitive and negative symptoms of the disorder are poorly understood but are particularly difficult to treat. Not only do these symptoms dramatically affect day-to-day functioning, they are largely intractable to antipsychotic medications targeting the dopamine D2 receptor, which only ameliorate the positive symptoms of the disorder. As such, the severity of cognitive and negative symptoms is a better predictor for the long-term prognosis of patients than the degree of positive symptoms. It is important to note however, that deficits in working memory and motivation are not specific to schizophrenia, but are also present in other mental disorders such as depression and ADHD. In this context, the work in my laboratory has broader applications, revealing both normal and aberrant brain function relevant to mental disorders characterized by deficits in cognitive and motivational behaviors.
To tie this research closely to disease-relevant brain circuitry, our approach uses observations made in patients with schizophrenia and then seeks to “model” these observations as closely as possible in the mouse. This allows for determining how an alteration can cause changes in brain function and behavior – a major limitation of human studies where findings are by and large correlational. Using this approach we hope to achieve three main goals:
- To better understand the basic mechanisms that regulate cognitive and motivated behaviors relevant for schizophrenia
- To inspire new human studies based on outcomes from our mouse models
- To develop new treatment strategies for enhancing cognition and motivation
- Canetta S, Sourander A, Surcel HM, Hinkka-Yli-Salomäki S, Leiviskä J, Kellendonk C, McKeague IW, Brown AS (2014) Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort. Am J Psychiatry. 2014 Jun 27. doi: 10.1176/appi.ajp.2014.13121579
- Canetta SE, Bao Y, Co MD, Ennis FA, Cruz J, Terajima M, Shen L, Kellendonk C, Schaefer CA, Brown AS. (2014) Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring Am J Psychiatry. 171:557-63.
- Simpson EH, Morud J, Winiger V, Biezonski D, Zhu JP, Bach ME, Malleret G, Polan HJ, Ng-Evans S, Phillips PE, Kellendonk C, Kandel ER. (2014) Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum. Learn Memory. 21:205-14.
- Cazorla, F. de Carvalho, M. Chohan, M. Shegda, N. Chuhma, S. Rayport, S. Ahmari, H. Moore, C. Kellendonk (2014) Dopamine D2 receptors regulate the anatomical balance of basal ganglia circuitry Neuron 81:153-64.
- Parnaudeau, K.Taylor, S.S. Bolkan, R.D. Ward, P.D. Balsam1 and C. Kellendonk (2015) Mediodorsal Thalamus Hypofunction Impairs Flexible Goal-Directed Behavior. Biological Psychiatry 77:445-53 PMC4177020
- Biezonski D.K., Trifilieff P., Meszaros J., Javitch J.A., Kellendonk C (2015) Evidence for Limited D1 and D2 Receptor Co-Expression and Co-Localization Within the Dorsal Striatum of the Neonatal Mouse J. Comp. Neurology Dec 30. doi: 10.1002/cne.23730 PMID: 25556545
- Frederick A.L., Yano H., Trifilieff P., Vishwasrao H., Biezonski D., Mészáros J., Sibley D.R., Kellendonk C., Sonntag K.C., Graham D.V., Colbran R.J., Stanwood G.D, Javitch J.A. (2015) Re-evaluating dopamine D1/D2 receptor heteromerization, pharmacology and signaling in vitro and in vivo Molecular Psychiatry Jan 6. doi: 10.1038/mp.2014.166. PMID: 25560761
- E.F. Gallo, M.C. Salling, B. Feng, J.A. Morón, N.L. Harrison, J.A. Javitch, C. Kellendonk. (2015) Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology Jan 12. doi: 10.1038/npp.2015.11. PMID:25578797
- R01 MH093672-01 (Kellendonk, PI) 05/20/2011-03/31/2016NIMH
- 1P50MH086404-01A1 (Abi-Dargham, PI) 07/01/2010-03/31/2015NIMH Silvio O. Conte Center,
“Dopamine Dysfunction in Schizophrenia”: Project 4: “The Role of Striatal Postsynaptic Dopamine Receptor Activity in the Cognitive Symptoms of Schizophrenia”
“Medium spiny Neuron Excitability and Motivation”
- Irma T. Hirschl Research Awards (Kellendonk, PI) 04/01/2014-31/03/2019Irma T. Hirschl Trust
“Identifying neuronal circuits and mechanisms of working memory”
- 2014 Irving Institute CaMPR-BASIC Pilot Grant 08/01/2014-07/31/2015Irving Institute for Clinical and Translational Research
“The relationship between prenatal immune activation and basal metabolism in the adolescent hippocampus”
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