Monoaminergic Modulation of Prefrontal Cortex

Project: Research project

Project Details

Description

DESCRIPTION: Disordered dopamine signaling has long been known to be a critical factor in the etiology of schizophrenia. This view is based upon several key observations. Foremost among them is the ability of neuroleptics that antagonize DA receptors to alleviate the positive symptoms of schizophrenia. However, in recent years, the exclusive involvement of DA in schizophrenia has been questioned. In part, the clinical effectiveness of atypical neuroleptics like clozapine has motivated this new line of thought. The ability of atypical neuroleptics to antagonize both DA receptors and serotonin receptors is generally thought to be critical to their efficacy. Although there is evidence for altercations in neuronal function at several levels of the neuroaxis in schizophrenia, most experimental evidence points to the prefrontal cortex. It is the central hypothesis of this proposal that the cognitive deficits observed in schizophrenics and their close relatives are a direct consequence of altered DA and 5-HT signaling within the prefrontal cortex. This disruption may have a common cellular locus-that is, interactions between these two monoamines at the single cell level may be responsible for the pathophysiology in schizophrenia. However, at present there are fundamental gaps in our understanding of how DA and 5-HT regulate neural activity in the PFC. To begin to fill these gaps, we propose to apply a combination of electrophysiological, anatomical, pharmacological and molecular techniques to achieve four specific aims. Our initial aim is to use single cell RT-PCR techniques and retrograde labeling to identify the DA and 5-HT receptors expressed by PFC pyramidal neurons participating in circuits thought to be affected in schizophrenia. Next, the impact of D1/D5 DA receptors on voltage-dependent Na and Ca channels will be determined in retrogradely identified PFC pyramidal neurons using a combination of RT-PCT, voltage-clamp and fluorometry. In parallel, the modulatory effects of 5-HT-2 receptors on these same channel populations will be determined using a similar combination of techniques. Lastly, the nature of the interaction between these two schizophrenia linked signaling pathways in the modulation of Na and Ca channels will be determined. It is our thesis that these two pathways synergistically interact in ways critical to the disease process. Achieving these specific aims will provide the molecular and cellular framework necessary to begin building an accurate, integrative model of PFC function and dysfunction in schizophrenia.
StatusFinished
Effective start/end date9/1/002/28/06

Funding

  • National Institute of Mental Health (5 R01 MH062070-05)

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