Homer expression in the Xenopus tadpole nervous system.

Homer proteins are integral components of the postsynaptic density and are thought to function in synaptogenesis and plasticity. In addition, overexpression of Homer in the developing Xenopus retinotectal system results in axonal pathfinding errors. Here we report that Xenopus contains the homer1 gene, expressed as the isoform, xhomer1b, which is highly homologous to the mammalian homer1b. The mammalian homer1 gene is expressed as three isoforms, the truncated or short form homer1a and the long forms homer1b and -1c. For Xenopus, we cloned three very similar variants of homer1b, identified as Xenopus xhomer1b.1, xhomer1b.2, and xhomer1b.3, which display up to 98% homology with each other and 90% similarity to mammalian homer1b. Furthermore, we demonstrate that Xenopus also contains a truncated form of the Homer1 protein, which could be induced by kainic acid injection and is likely homologous to the mammalian Homer1a. xHomer1b expression was unaffected by neuronal activity levels but was developmentally regulated. Within the brain, the spatial and temporal distributions of both Homer isoforms were similar in the neuropil and cell body regions. Homer1 was detected in motor axons. Differential distribution of the two isoforms was apparent: Homer1b immunoreactivity was prominent at junctions between soma and the ventricular surface; in the retina, the Mueller radial glia were immunoreactive for Homer1, but not Homer1b, suggesting the retinal glia contain only the Homer1a isoform. Homer1b expression in muscle was prominent throughout development and was aligned with the actin striations in skeletal muscle. The high level of conservation of the xhomer1 gene and the protein expression in the developing nervous system suggest that Homer1 expression may be important for normal neuronal circuit development.

Homer proteins regulate sensitivity to cocaine.

Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.