The Silvio O. Conte center dopamine dysfunction in Schizophrenia

nyspifacadefaded The Silvio O. Conte Center
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Participate in a brain imaging study

Project 4
The Role of Striatal Postsynaptic Dopamine D2 Receptor Activity in the Cognitive Symptoms of Schizophrenia

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Human brain imaging studies by the investigators of P1 have shown that, in people with schizophrenia, release of the neurotransmitter dopamine, as well as the levels of the D2 type dopamine receptor in the striatum are elevated, resulting in a higher occupancy of these receptors (1-3). However, human brain imaging techniques are not able to reveal which particular symptoms of the illness may originate from increased dopamine D2 receptor activation in the striatum. To test the possibility of a direct cause-effect relationship, we generated a line of genetically modified mice with increased dopamine D2 receptor expression that is restricted to the striatum and can be regulated in time (4). We have shown that striatal D2 receptor upregulation during prenatal development leads to persistent cognitive deficits in adulthood. These cognitive deficits are not general, but strikingly share similarities with the types of cognitive deficits commonly suffered by people with schizophrenia, such as deficits in working memory, conditional associative learning, behavioral flexibility and interval timing (4-7). Our studies have also revealed that the mice exhibit changes in dopamine function in the prefrontal cortex (4), the brain structures known to operate the particular cognitive functions that are disrupted.

A convergence of these findings with data from the primate and human projects from the previous Conte Center at Columbia has led us to propose that striatal dopamine dysregulation may be a pathogenic mechanism leading to prefrontal cortical circuit dysfunction and disordered cognitive control in schizophrenia (8). Since the cognitive symptoms of schizophrenia are largely resistant to currently available medications, understanding the disease mechanisms leading to prefrontal cortical circuit dysfunction and disordered cognitive control in schizophrenia is crucial for the development of better treatment strategies for patients with schizophrenia. Our mouse studies illustrate, perhaps for the first time, that the reason that the cognitive symptoms of schizophrenia are resistant to treatment by D2 blocking antipsychotic drugs, may be due to the fact that secondary, compensatory changes have occurred early in development. A detailed understanding of the molecular alterations during early development that lead to these compensatory changes may reveal potential drug targets to counteract them in adulthood or possibly to prevent their occurrence during early development altogether. Therefore, it is the goal of P4 to determine the molecular and cellular steps by which increased D2 receptor expression in the striatum disrupts normal dopamine function in the prefrontal cortex, and in turn results in the cognitive symptoms of schizophrenia.
 

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The researchers involved with project 4 are: PI Eric R. Kandel, Co-PI Jonathan Javitch, Co-investigators Eleanor Simpson and Christoph Kellendonk.

References

  1. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235-9240. PMID: 8799184
     
  2. Laruelle M (1998) Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 42:211-221.PMID: 9796369
     
  3. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97:8104-8109. PMID: 10884434
     
  4. Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49:603-615. PMID: 16476668
     
  5. Bach M-E, Simpson EH, Kahn L, Marshall JJ, Kandel ER, Kellendonk C (2008) Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning. Proc Natl Acad Sci U S A 105:16027-16032.PMID: 18832466
     
  6. Drew MR, Simpson EH, Kellendonk C, Herzberg WG, Lipatova O, Fairhurst S, Kandel ER, Malapani C, Balsam PD (2007) Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci 27:7731-7739.PMID: 17634367
     
  7. Ward RD, Kellendonk C, Simpson EH, Lipatova O, Drew MR, Fairhurst S, Kandel ER, Balsam PD (2009) Impaired timing precision produced by striatal D2 receptor overexpression is mediated by cognitive and motivational deficits. Behav Neurosci 123:720-730.PMID: 19634929
     
  8. Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65:585-596.PMID: 20223196

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