Recent evidence suggests that aspects of drug abuse and addiction may be mechanistically understood as drug-induced neural plasticity. Immediate early genes (IEGs) are believed to play a role in mediating stimulus-induced changes in gene expression that underlie the long-term neurochemical and behavioral effects of cocaine. Our laboratory has identified a novel brain IEG, termed Homer, which appears to function at excitatory synapses where it interacts with metabotropic glutamate receptors. Metabotropic receptors are enriched in neurons of the striatum and are known to play an important role in long-term neuronal plasticity and in reward behaviors. The rapid induction of Homer in the striatum by cocaine is therefore likely to be important in long-term adaptive responses. Our approach to understand the function of Homer utilizes recent advances in knockout and transgenic technologies.
Aim 1 will generate and examine Homer """"""""knockout"""""""" mice. Knockouts are anticipated to provide essential information regarding the role of Homer in forebrain development and test the hypothesis of a selective role for Homer in activity-dependent modification of excitatory synapses.
Aim 2 will generate transgenic mice that express epitope-tagged, wild-type Homer in brain neurons and evaluate the consequences of constitutive over expression. We hypothesize that these mice will exhibit an alteration in their ability to modify excitatory synapses in responses to neuronal activity and this will consequently modify chronic responses to cocaine.
Aim 3 will generate mice that conditionally express wild-type Homer. These studies will test the reversibility of findings from Aim 2 and confirm their dependence on Homer expression. Additionally, these mice will permit us to explore novel mechanisms involved in the targeting of Homer protein to excitatory synapses.
Aim 4 will generate mice that express a mutant form of Homer that does not bind mGluR to test the hypothesis that phenotypic changes assayed in Aims 2 and 3 are due to the ability of Homer to interact with the mGluR. These studies may identify a specific protein-protein interaction that could ultimately be targeted as a therapeutic approach to modify cocaine-induced behaviors.
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