Behavioral data suggest the presence of a decrease in dopamine (DA) tone in the RFC in schizophrenia, consistent with morphological evidence of a decrease in the RFC DA innervation. Postmortem studies of schizophrenia have noted a decrease in PFC volume that is not due to a loss of neurons, but rather a decrease in neuropil, suggesting changes in the size of cell bodies, a decrease in presynaptic elements, or a pruning of the dendritic trees of neurons. Several groups have reported that the basal dendrites of PFC pyramidal cells are truncated and have a decreased density of dendritic spines. In striatal medium spiny neurons, which have the same synaptic architecture of DA axons and dendritic spines in PFC pyramidal cells, DA denervation causes a decrease in dendritic spine density and length. Our preliminary data indicate that cortical DA depletion also causes a reduction in dendritic length and spine density in the basal dendrites of layer V pyramidal cells in the PFC. We hypothesize that a decrease in PFC DA results in remodeling of pyramidal cell dendrites. We propose to determine if DA denervation of the PFC in rodents results in dendritic remodeling of PFC pyramidal cells, and assess if pyramidal cells differ in their response to DA denervation based on their projection targets. In order to determine which DA receptor(s) is involved in DA denervation-induced dendritic remodeling, we will examine the effects of DA receptor antagonists and use DA receptor knockout mice. We will also determine if loss of signaling through the alpha 2c adrenergic receptor, for which DA has low nanomolar affinity, is involved. Finally, we will determine if DA denervation- induced morphological alterations in PFC pyramidal cells can be reversed by chronic treatment with dopamine agonists or atypical antipsychotic drugs, which increase extracellular DA levels in the PFC. These studies will reveal the mechanisms underlying the dendritic reorganization of prefrontal cortical neurons, and may offer insights into new approaches for slowing cortical loss and the treatment of cognitive dysfunction in schizophrenia.

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National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Nadler, Laurie S
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Vanderbilt University Medical Center
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