The dopamine hypothesis remains a prominent influence on research into the pathophysiology of schizophrenia (SCHIZ), yet the presence of consistent SCHIZ-linked abnormalities either in the presynaptic components of the dopamine system or in dopamine receptors (DRs) still remains a matter of debate. The present proposal focuses on a recently recognized group of DR-interacting proteins (DRIPs) as possible novel sites of dysfunction in SCHIZ. In pursuing this hypothesis, we have already demonstrated that the dorsolateral prefrontal cortex from SCHIZ cases of the Stanley Foundation Neuropathology Consortium express significantly increased levels of the D 1 DRIP, calcyon, and the D2 DRIP, NCS-1. These findings support our proposition that SCHIZ is associated with altered levels of specific DRIPs. It is also interesting that these two proteins strongly associate with Ca2+ signaling. Therefore, they have joined the growing list of molecules involved in Ca2+ signaling and whose abnormalities have been reported in SCHIZ. Consequently, our data uphold the central hypothesis of our Center that SCHIZ, while may be induced by multifactorial causes, is, at its core, a disease of Ca2+ signaling. The main goal of this project is to confirm and expand our examinations of DRIPs in SCHIZ, which is essential for proving both the specific hypothesis of this project and the general hypothesis of the entire Center. This will be achieved in the following specific aims: 1. We will determine whether in SCHIZ patients levels of calcyon and NCS-1 are affected in areas other than the previously-examined dorsolateral prefrontal cortex. We will also examine whether the changes in these DRIPs could be consistently observed in samples from several brain collections. 2. We will determine whether detected changes in levels of calcyon and NCS-1 proteins are associated with increased transcription of these DRIPs by regional cells. 3. We will analyze possible SCHIZ-linked changes in the proportion of calcyon- and NCS-1-containing neurons and glia among the cells of specific brain regions and their structural subdivisions. 4. We will conduct a detailed examination of the cellular and subcellular distributions of calcyon and NCS-1 in specific regions of the primate brain. 5. We will continue to evaluate additional novel DRIPs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH068789-01
Application #
6892731
Study Section
Special Emphasis Panel (ZMH1-BRB-P (04))
Project Start
2003-12-12
Project End
2005-11-30
Budget Start
2003-12-12
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$178,200
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
El-Hassar, Lynda; Simen, Arthur A; Duque, Alvaro et al. (2014) Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels. Biol Psychiatry 76:476-85
Xiao, Jiping; Bergson, Clare (2013) Detection of cell surface dopamine receptors. Methods Mol Biol 964:3-13
Urban, Kimberly R; Gao, Wen-Jun (2013) Methylphenidate and the juvenile brain: enhancement of attention at the expense of cortical plasticity? Med Hypotheses 81:988-94
Wang, H-X; Waterhouse, B D; Gao, W-J (2013) Selective suppression of excitatory synapses on GABAergic interneurons by norepinephrine in juvenile rat prefrontal cortical microcircuitry. Neuroscience 246:312-28
Driesen, N R; McCarthy, G; Bhagwagar, Z et al. (2013) Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry 18:1199-204
Driesen, Naomi R; McCarthy, Gregory; Bhagwagar, Zubin et al. (2013) The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology 38:2613-22
Muthusamy, Nagendran; Faundez, Victor; Bergson, Clare (2012) Calcyon, a mammalian specific NEEP21 family member, interacts with adaptor protein complex 3 (AP-3) and regulates targeting of AP-3 cargoes. J Neurochem 123:60-72
El-Hassar, Lynda; Hagenston, Anna M; D'Angelo, Lisa Bertetto et al. (2011) Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca²? wave-dependent activation of SK and TRPC channels. J Physiol 589:3211-29
Arnsten, Amy F T (2011) Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry 69:e89-99
Vazdarjanova, A; Bunting, K; Muthusamy, N et al. (2011) Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood. Mol Psychiatry 16:672-84

Showing the most recent 10 out of 57 publications