Recent studies implicate immediate early genes (IEGs) in drug addiction. Our laboratory has focused on an IEG termed Homer1a that is rapidly induced by cocaine. A family of Homer proteins has now been identified that bind receptors for group 1 metabotropic glutamate (mGluR) and inositol trisphosphate (IP3R). Homer proteins also interact with scaffolding proteins involved in NMDA receptor signaling. Cell biological studies support the hypothesis that Homer proteins function as an adapter system to regulate the coupling of intracellular calcium pools with membrane receptors, and may additionally play a role in receptor trafficking and synaptogenesis. The IEG form (Homer 1a) appears to function as natural dominant negative that disrupts crosslinking. This biochemical competition provides a mechanism by which natural synaptic activity can modify synaptic function. Studies conducted with the support of this grant have focused on generating mouse models to test the integrated cellular and systems-level functions of Homer. We generated transgenic mice that constitutively express Homer 1a, and used these mice to support the """"""""dominate negative"""""""" hypothesis. We also generated knockouts (ko) of Homer 2 and 3, and will soon have a conditional ko of Homer 1. Initial analysis indicates that Homer 2 and 3 ko mice are viable.
In Aim 1 we will use ko mice to examine the consequence of deleting Homer proteins. Because Homer proteins are biochemically redundant, our strategy includes generating mice with combined deletions of multiple Homer proteins. These mouse models will be the basis for understanding the contribution of crosslinking forms of Homer to both cellular (calcium signaling, trafficking and synaptogenesis) and systems-level (cocaine sensitization and learning) functions.
Aim 2 will examine the function of the IEG form of Homer. We will use a new strategy that is designed to overcome limitations of current transgenic models, which exhibit mosaic expression of the transgene. Homer 1a will be expressed using a bacterial artificial chromosome (bac) of CaMKII. In parallel, we will generate a selective deletion mutant for Homer 1a. These mouse models will be used in physiological and behavioral studies to test and refine the dominant negative model of Homer IEG function. Thus, experiments in Aim 1 will tell us what crosslinking Homer proteins do, while Aim 2 will tell us what aspects of Homer function can be modulated in response to neuronal activity. Together, these studies will provide fundamental insight into how stimuli such as cocaine can effect long-term changes in synaptic and brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011742-08
Application #
6898947
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (03))
Program Officer
Satterlee, John S
Project Start
1998-07-01
Project End
2006-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
8
Fiscal Year
2005
Total Cost
$408,750
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51
Cozzoli, Debra K; Courson, Justin; Wroten, Melissa G et al. (2014) Binge alcohol drinking by mice requires intact group 1 metabotropic glutamate receptor signaling within the central nucleus of the amygdala. Neuropsychopharmacology 39:435-44
Obara, Ilona; Goulding, Scott P; Hu, Jia-Hua et al. (2013) Nerve injury-induced changes in Homer/glutamate receptor signaling contribute to the development and maintenance of neuropathic pain. Pain 154:1932-45
Park, Joo Min; Hu, Jia-Hua; Milshteyn, Aleksandr et al. (2013) A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization. Cell 154:637-50
Cozzoli, Debra K; Courson, Justin; Caruana, Amanda L et al. (2012) Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures. Alcohol Clin Exp Res 36:1623-33
Hu, Jia-Hua; Park, Joo Min; Park, Sungjin et al. (2010) Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron 68:1128-42
Shin, J H; Kim, Y S; Worley, P F et al. (2009) Depolarization-induced slow current in cerebellar Purkinje cells does not require metabotropic glutamate receptor 1. Neuroscience 162:688-93
Cozzoli, Debra K; Goulding, Scott P; Zhang, Ping Wu et al. (2009) Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism. J Neurosci 29:8655-68
Gerfen, Charles R; Paletzki, Ronald; Worley, Paul (2008) Differences between dorsal and ventral striatum in Drd1a dopamine receptor coupling of dopamine- and cAMP-regulated phosphoprotein-32 to activation of extracellular signal-regulated kinase. J Neurosci 28:7113-20
Szumlinski, Karen K; Kalivas, Peter W; Worley, Paul F (2006) Homer proteins: implications for neuropsychiatric disorders. Curr Opin Neurobiol 16:251-7

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