Homer2 Is Necessary for EtOH-Induced Neuroplasticity

Szumlinski, Karen K.; Lominac, Kevin D.; Oleson, Erik B.; Walker, Jennifer K.; Mason, Ashley R.; Dehoff, Marlin H.; Klugman, Matthias; Cagle, Stephanie; Welt, Kristine; During, Matthew J.; Worley, Paul F.; Middaugh, Lawrence D.; Kalivas, Peter W.

doi:10.1523/jneurosci.1529-05.2005

Cited by 146 publications

(328 citation statements)

References 35 publications

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“…Deletion of Homer2 in mice reveals that Homer2 is involved in appetitive pathways that underlie responses to cocaine and alcohol [32][33][34]. The alcohol and cocaine phenotypes of the Homer2 −/− mice are consistent with enhanced response to the drugs.…”

Section: Homer 2 and Rgs Proteins Gap Activitymentioning

confidence: 92%

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Homer proteins in Ca2+ signaling by excitable and non-excitable cells

et al. 2007

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Homers are scaffolding proteins that bind Ca 2+ signaling proteins in cellular microdomains. The Homers participate in targeting and localization of Ca 2+ signaling proteins in signaling complexes. However, recent work showed that the Homers are not passive scaffolding proteins, but rather they regulate the activity of several proteins within the Ca 2+ signaling complex in an isoform specific manner. Homer2 increases the GAP activity of RGS proteins and PLCβ that accelerate the GTPase activity of Gα subunits. Homer1 gates the activity of TRPC channels, controls the rates of their translocation and retrieval from the plasma membrane and mediates the conformational coupling between TRPC channels and IP 3 Rs. Homer1 stimulates the activity of the cardiac and neuronal Ltype Ca 2+ channels Ca v 1.2 and Ca v 1.3. Homer1 also mediates the communication between the cardiac and smooth muscle ryanodine receptor RyR2 and Ca v 1.2 to regulate E-C coupling. In many cases the Homers function as a buffer to reduce the intensity of Ca 2+ signaling and create a negative bias that can be reversed by the immediate early gene form of Homer 1. Hence, the Homers should be viewed as the buffers of Ca 2+ signaling that ensure a high spatial and temporal fidelity of the Ca 2+ signaling and activation of downstream effects.

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Section: Homer 2 and Rgs Proteins Gap Activitymentioning

confidence: 92%

“…The functional role of Homer2 has been examined in the brain [32,33] and the pancreas [30]. Deletion of Homer2 in mice reveals that Homer2 is involved in appetitive pathways that underlie responses to cocaine and alcohol [32][33][34].…”

Section: Homer 2 and Rgs Proteins Gap Activitymentioning

confidence: 99%

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

et al. 2007

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“…AAV infusion procedures were similar to those employed previously in mice (Szumlinski et al, 2004a(Szumlinski et al, , 2005b. In brief, rats were lightly restrained for a bilateral infusion of an AAV, conducted at a rate of 0.05 ml/min for 5 min (total volume ¼ 0.25 ml/side).…”

Section: Aav and Tat Infusionmentioning

confidence: 99%

“…After fixation, the brains were sectioned along the coronal plane on a vibratome at the level of the nucleus accumbens (100 mm; AP: + 2.2 to 1.0 mm, relative to bregma), according to the atlas of Paxinos and Watson (1986). Sections from AAV-Homer or Tat-Homer infused rats were stained with an antibody against the HA tag using standard immunocytochemical techniques as described previously for rats and mice (Klugmann et al, 2005;Szumlinski et al, 2004aSzumlinski et al, , 2005b and examined for transfection under a light microscope. Sections from AAV-GFP infused rats were examined for cellular transfection using a fluorescent microscope.…”

Section: Verification Of Transfectionmentioning

confidence: 99%

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

Szumlinski

Abernathy

Oleson

et al. 2005

Neuropsychopharmacol

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Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.

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“…The Homer family of proteins are encoded by 3 genes (Homer1-3) (Soloviev et al, 2000) and act to coordinate synaptic proteins for a variety of cellular functions, including calcium signaling and activity-dependent synaptic remodeling (for reviews, see de Bartolomeis and Iasevoli, 2003;Duncan et al, 2005;Fagni et al, 2002;Xiao et al, 2000). Homer proteins regulate signaling through, and the trafficking of, Group1 metabotropic glutamate receptors and N-methyl-D-aspartic acid (NMDA) receptors (eg Naisbitt et al, 1999;Shiraishi et al, 2003;Smothers et al, 2005;Szumlinski et al, 2004Szumlinski et al, , 2005bTu et al, 1998Tu et al, , 1999Xiao et al, 1998). Such regulation is of potential relevance to the neurobiology of alcoholism as these glutamate receptors are two sites of action for alcohol in the brain (eg Lovinger, 1996;Minami et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

Szumlinski

Ary

Lominac

et al. 2007

Neuropsychopharmacol

178

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Homer proteins are integral components of the postsynaptic density that are necessary for alcohol-induced neuroplasticity within the nucleus accumbens (NAC). In this report, we describe the effects of chronic alcohol consumption upon NAC Homer expression and investigate the functional consequences of mimicking the alcohol-induced changes in Homer expression vis-à-vis alcohol-induced changes in NAC neurochemistry and behavior. Chronic alcohol consumption under continuous access (3 months; daily intake E11.271.5 g/kg/ day) produced a robust increase in NAC Homer2 protein levels that was apparent at 2 days, 2 weeks, and 2 months following withdrawal from alcohol drinking. The increased Homer2 expression was accompanied by a less enduring elevation in total mGluR1 and NR2b levels that were evident at 2 days and 2 weeks but not at the 2-month time point. Mimicking the alcohol-induced increase in Homer2 levels by viral transfection of NAC neurons in alcohol-preferring C57BL/6J inbred mice enhanced behavioral output for alcohol reinforcement and increased alcohol intake under both preprandial and postprandial conditions. Moreover, NAC Homer2 overexpression facilitated the expression of an alcohol-conditioned place preference, as well as the development of motor tolerance. Finally, NAC Homer2 overexpression facilitated NAC glutamate and dopamine release following an acute alcohol injection and augmented alcohol-induced dopamine and glutamate sensitization, but did not affect NAC g-aminobutyric acid levels. Thus, an upregulation in NAC mGluR-Homer2-N-methyl-D-aspartic acid receptor signaling appears to be an important molecular adaptation to alcohol that promotes neuroplasticity facilitating motivational drive for alcohol and the development of alcoholism-related behaviors.

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Homer2 Is Necessary for EtOH-Induced Neuroplasticity

Cited by 146 publications

References 35 publications

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

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