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 5
Dopamine Neuron Transmission, Imaging Endophenotypes and the Diathesis of Schizophrenia

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While dopamine (DA) signaling is clearly altered in schizophrenia, it is by no means clear whether this is the direct cause of symptoms, or whether altered patterns of DA neuron activity earlier in life have induced pathological circuitry alterations, which later on prove pathogenic. To address these issues, we are using transgenic strategies in mice to alter DA reuptake and DA neuron spike firing patterns in order to modulate tonic DA levels and phasic DA transmission selectively. To produce increased tonic DA, we are using mice with reduced DA transporter (DAT) function due to the introduction of the cre allele into the DAT locus. To bi-directionally modulate phasic DA, we are using mice in which the key NR1 subunit of the NMDA receptor is deleted just in DA neurons to block burst firing, and mice in which the SK3 channel is deleted to enhance burst firing.

We will first show that the mice have the expected alterations in DA neuron activity assessed with extracellular single-unit recordings in anesthetized mice, in basal DA release assessed with microdialysis in awake mice, and in event-related release as measured with voltammetry, in anesthetized mice with manipulations known to increase burst firing, and then in awake, freely-moving mice during presentation of appetitively conditioned stimuli. Second, we will ask which alterations in DA neuron activity, involving basal DA tone or phasic firing, translate into the imaging endophenotypes of schizophrenia, using ex-vivo approaches and microPET. Third, in models in which changes in tonic and event-related DA efflux have been validated, we will determine how changes in these modes of DA transmission affect behavioral and cognitive processes relevant to schizophrenia, focusing on incentive learning and working memory. By virtue of the stronger expression of DAT and SK3 in subcortically projecting DA neurons, we will be able to address whether increased tonic or phasic striatal DA impairs cortical function. Fourth, in an exploratory aim, we will use inducible transgenic strategies to address the pathogenic vs. pathophysiological roles of altered DA neuron transmission.

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DAT knockdown and dopamine neuron actvity. In DAT cre (DAT knockdown) and DAT-IRES cre (control) mice, whole cell patch clamp recordings were obtained from identified dopamine (DA) neurons in horizontal slices encompassing the Ventral Tegmental Area (VTA) and Substantia Nigra (SN). Representative traces of DA neuron spontaneous activity are shown on the left and the cumulative probability of Inter-spike intervals on the right. The DAT knockdown increases the firing rate of DA neurons in the SN but does not induce burst firing, indicating that tonic and phasic DA neuron firing can be modulated separately.

The researchers involved with Project 5 are: PI Stephen Rayport, Co-PI Holly Moore, Co-investigators Nao Chuhma and Susana Mingote, Collaborating investigators Peter Balsam, Jay A. Gingrich, David Sulzer, John Adelman and Marc Laruelle and Consultant Paul D. Shepard.

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