P1-024: Altered dopamine receptor immunoreactivity in CNS of transgenic mice overexpressing alpha-synuclein

Abstract

Transgenic mice overexpressing wild–type human alpha–synuclein (α–syn) exhibit α–syn immunopositive inclusions and neurites in multiple regions of the brain including the hippocampus, cerebellum and cortex. Drawing on the methods of multi–scale imaging, behavioral pharmacology and bioinformatics, we are using a multi–disciplinary approach to characterize a transgenic mouse overexpressing human α–syn. We previously reported alterations in cognitive and motor behaviors, and increased metabotropic glutamate, subtype 5 (mGluR5) immunoreactivity in the CNS of α–syn transgenic mice. In addition to dopamine (DA) receptor agonists, mGluR5 antagonists have received interest as a therapeutic target for Parkinsonian motor dysfunction via restoration of dopamine–glutamatergic homeostasis. While the basis for mGluR5 antagonist induced amelioration of PD symptoms is not clearly understood, most PD researchers appreciate that the complexity of clinical cognitive and motor symptoms are the result of complex changes in many regions and neurotransmitter systems. Accordingly, alterations in adenosine, serotonin, GABA, and dopamine receptors have been reported in PD patients. Of these, alterations in dopamine D1 and D2 receptors have been observed in patients, and have been investigated in PD animal models. Assessment of dopamine D1 and D2 receptor expressions is a necessary first step towards validation of any animal model for preclinical assessment of dopamine D1/D2 receptor agonists. With this consideration, we conducted multi–scale imaging studies of dopamine D1 and D2 receptor immunolabeling in the α–syn transgenic model of PD, using both laser scanning confocal and multi–photon microscopy. Here we report our findings of PD–like increases in striatal dopamine D1 receptors in α–syn transgenic animals. Studies of dopamine D2 receptor levels and distribution are underway. Taken together, these results suggest that PD–like alterations in glutamatergic and dopaminergic neurotransmission are recapitulated in the α–syn transgenic model of PD, and further that this animal model is an appropriate system for preclinical assessment of mGluR5 and DA receptor ligands.