The Center on """"""""Dopamine Dysfunction in Schizophrenia"""""""" will test the central hypothesis that striatal dopaminergic hyperactivity during development leads to prefrontal cortical dopamine (DA) dysfunction in schizophrenia (SCZ) and the cognitive deficits that characterize the disorder. Thus, dysregulation of DA transmission in the striatum during development and its ultimate effect on prefrontal cortical (PFC) DA transmission and PFC circuit function contribute to positive symptoms, negative symptoms and cognitive deficits. This hypothesis is based on a convergence of recent findings from Center investigators: 1) the striatal DAergic excess in schizophrenia is greatest in the associative striatum (AST), 2) the AST receives convergent input from dorsolateral-prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC) and limbic frontal cortical regions, rendering it crucial for integration of affective and cognitive processes, 3) striatal DA D2 receptor overexpression during development in mice results in frontal cortical dopamine alterations, PFC dysfunction, as evidenced by irreversible learning deficits, as well as rnotivational and social deficits. Thus,integration of incoming information from the PFC may be altered by excessive D2 signaling in the associative striatum, which impairs cortical flow of information across cortico-striato-pallido-thalamo-cortical loops and alters midbrain DA function. Our five Projects supported by 4 Cores are organized to test this hypothesis. We will test in patients with SCZ compared to healthy controls whether the striatal DA pathology predicts: 1) cortical DA pathology measured with Positron Emission Tomography (PET) (P1) and 2) PFC-mediated cognitive functioning as assessed with working memory tasks and the associated changes in PFC activity as measured with Functional Magnetic Resonance Imaging (fMRI) (P2). We will create transgenic mice with early developmental overexpression of D2 receptors in striatum (P4) or alterations in midbrain DA firing patterns and striatal DA release (P5). These mouse models will be used to understand possible mechanisms underlying abnormal frontal cortical DA transmission as well as cognitive and behavioral abnormalities mediated by PFC-striatal circuits in SCZ. We will also determine the critical alterations in signal transduction in the striatum mediating these effects (P4), the underlying circuitry both in monkeys and in rodents (P3), and possible neurochemical mediators of DA imaging endophenotypes associated with SCZ (P5). This set of studies in humans, monkeys and mice will establish the role of striatal DA dysregulation in the pathogenesis of PFC dysfunction in SCZ, and by doing so will serve as a critical first step to novel approaches to treatment that interrupt this pathogenic mechanism.
Disordered cognition leads to severe functional impairment in schizophrenia. Our new perspective on a key alteration in this illness, which is DA dysfunction, and the set of mechanistic studies we propose in order to test it, will lead to new and better understanding of the disorder. This in turn may lead to preventive or therapeutic strategies that can be developed based on this new understanding.
|Weinstein, J J; van de Giessen, E; Rosengard, R J et al. (2018) PET imaging of dopamine-D2 receptor internalization in schizophrenia. Mol Psychiatry 23:1506-1511|
|Cassidy, Clifford M; Balsam, Peter D; Weinstein, Jodi J et al. (2018) A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine. Curr Biol 28:503-514.e4|
|Sykes, David A; Moore, Holly; Stott, Lisa et al. (2017) Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat Commun 8:763|
|Simpson, Eleanor H; Kellendonk, Christoph (2017) Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation. Biol Psychiatry 81:21-30|
|Chuhma, Nao; Mingote, Susana; Kalmbach, Abigail et al. (2017) Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia. Biol Psychiatry 81:43-51|
|Mingote, Susana; Chuhma, Nao; Kalmbach, Abigail et al. (2017) Dopamine neuron dependent behaviors mediated by glutamate cotransmission. Elife 6:|
|Weinstein, Jodi J; Chohan, Muhammad O; Slifstein, Mark et al. (2017) Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biol Psychiatry 81:31-42|
|Cassidy, Clifford M; Van Snellenberg, Jared X; Benavides, Caridad et al. (2016) Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia. J Neurosci 36:4377-88|
|Horga, Guillermo; Cassidy, Clifford M; Xu, Xiaoyan et al. (2016) Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia. JAMA Psychiatry 73:862-70|
|Van Snellenberg, Jared X; Girgis, Ragy R; Horga, Guillermo et al. (2016) Mechanisms of Working Memory Impairment in Schizophrenia. Biol Psychiatry 80:617-26|
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