Schizophrenia is a mental disorder with devastating symptoms, yet, at the macroscopic level, the brains of schizophrenics are no different than the brains of healthy subjects. Recent electron microscope studies, however, revealed microscopic structural abnormalities that affect the dendrites of neocortical pyramidal neurons. Interestingly, distal parts of these dendrites of pyramidal cells are targets of dopaminergic axon terminals. Furthermore, in prefrontal cortex, an area implicated in pathophysiology of schizophrenia, individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes excitatory transmitter (glutamate), and the other one that secretes dopamine. It is thought that dopamine secretion is elevated in schizophrenia because dopamine receptor blockers alleviate some symptoms. Our working hypothesis is that abnormally high dopamine secretion suppresses dendritic excitability and severely disrupts information processing at the level of individual neurons (a process also know as integration of synaptic inputs). In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic inputs by delivering glutamate and dopamine pulses locally, onto individual dendritic branches (local application of neurotransmitters through glass pipettes). This approach allows precise control of the location of excitatory input to the dendritic tree, with precise timing, and most importantly, the role of presynaptic mechanisms in the interpretation of experimental results is eliminated. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the glutamate stimulation site, as well as in the neighboring dendrites that are exposed to neither glutamate nor dopamine. The proposed experiments are expected to yield a more complete picture of how local fluctuation in dopamine level can shape the information processing in individual neurons, and provide impetus for new therapeutic approaches in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063503-05
Application #
6921477
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Asanuma, Chiiko
Project Start
2001-08-10
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
5
Fiscal Year
2005
Total Cost
$253,750
Indirect Cost
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Antic, Srdjan D; Hines, Michael; Lytton, William W (2018) Embedded ensemble encoding hypothesis: The role of the ""Prepared"" cell. J Neurosci Res 96:1543-1559
Oikonomou, Katerina D; Singh, Mandakini B; Rich, Matthew T et al. (2015) Contribution of extrasynaptic N-methyl-D-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials. Philos Trans R Soc Lond B Biol Sci 370:
Popovic, Marko; Vogt, Kaspar; Holthoff, Knut et al. (2015) Imaging Submillisecond Membrane Potential Changes from Individual Regions of Single Axons, Dendrites and Spines. Adv Exp Med Biol 859:57-101
Zhou, Wen-Liang; Short, Shaina M; Rich, Matthew T et al. (2015) Branch specific and spike-order specific action potential invasion in basal, oblique, and apical dendrites of cortical pyramidal neurons. Neurophotonics 2:021006
Belinsky, Glenn S; Rich, Matthew T; Sirois, Carissa L et al. (2014) Patch-clamp recordings and calcium imaging followed by single-cell PCR reveal the developmental profile of 13 genes in iPSC-derived human neurons. Stem Cell Res 12:101-18
Zhou, Wen-Liang; Oikonomou, Katerina D; Short, Shaina M et al. (2013) Dopaminergic regulation of dendritic calcium: fast multisite calcium imaging. Methods Mol Biol 964:123-38
Oikonomou, Katerina D; Short, Shaina M; Rich, Matthew T et al. (2012) Extrasynaptic glutamate receptor activation as cellular bases for dynamic range compression in pyramidal neurons. Front Physiol 3:334
Zhou, Wen-Liang; Antic, Srdjan D (2012) Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons. J Physiol 590:3891-911
Moore, Anna R; Zhou, Wen-Liang; Potapenko, Evgeniy S et al. (2011) Brief dopaminergic stimulations produce transient physiological changes in prefrontal pyramidal neurons. Brain Res 1370:1-15
Moore, Anna R; Zhou, Wen-Liang; Jakovcevski, Igor et al. (2011) Spontaneous electrical activity in the human fetal cortex in vitro. J Neurosci 31:2391-8

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