Neurotransmitter receptors in three rodent models of Parkinson's disease : a quantitative multireceptor study
Year: 2013
Type: dissertation
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite ongoing efforts, the knowledge of the etiology and underlying mechanisms resulting in the neurodegenerative processes (e.g., loss of dopaminergic neurons) remains incomplete. Since therapeutic intervention is still limited to symptomatic relief and mainly focused on the dopamine system, the understanding of the role of other, non-dopaminergic systems during pathogenesis of PD has to be improved for identifying new targets for treatment. Neurotransmitter receptors are major targets for pharmaceutical interventions in numerous neurological and psychiatric disorders, since distinct changes of receptors are often found in such diseases. In case of PD, the dominant role of changes in dopaminergic neurotransmission is well known. The possible involvement of other transmitter systems and their receptors, however, is not well understood. Therefore, the aim of this study was the analysis of the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in the brains of three well established mouse models of PD. The Pitx3 aphakia mouse served as a model exhibiting crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Additionally, Parkin and DJ-1 knockout mice were analyzed as models for hereditary parkinsonism by exhibiting PD associated gene mutations. Quantitative receptor autoradiography was used to comprehensively investigate the density and distribution of glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine receptors in eleven different brain regions (i.e., the olfactory bulb, the motor, somatosensory, piriform and visual cortices, the hippocampal regions CA1, CA2/3 and dentate gyrus, the striatum, the substantia nigra and the cerebellum). Differential quantitative changes of neurotransmitter receptor densities were demonstrated for the three different animal models of PD compared to controls. In general, receptor density changes were similar between Parkin and DJ-1 knockout mice, indicating pathologic mechanisms occurring likewise in both models. GABAB receptor densities were increased in several regions of all investigated PD models (i.e., the piriform cortex, the dentate gyrus, the visual cortex and the substantia nigra). Thus, the increase in GABAB receptors seems to be a common reaction during pathogenesis of PD. The densities of nicotinic acetylcholine, serotonergic 5-HT1A and 5-HT2 receptors were demonstrated to be considerably reduced in Pitx3 aphakia mouse brains (i.e., the nicotinic acetylcholine receptor in the striatum, CA2/3 and the dentate gyrus; the serotonergic 5-HT1A receptor in the olfactory bulb, CA1 and the dentate gyrus; the 5-HT2 receptor in the striatum). A complex pattern of receptor changes in the striatum of Pitx3 aphakia, Parkin and DJ-1 knockout mice, respectively, correlates with the behavioral findings in these mice, and indicates differential interactions and dependencies between the different receptor systems in PD. Taken together, the present findings of neurotransmitter receptor density changes in Pitx3 aphakia, Parkin and DJ-1 knockout mice, respectively, provide novel data on the up- and down-regulation of GABA, acetylcholine, and 5-HT receptor expression in animal models of PD, and thereby highlight the often neglected impact of non-dopaminergic systems in the molecular pathology of Parkinson’s disease.
Source: RWTH Publications (RWTH Aachen)
Authors: Jennifer Nadine Cremer, H. N. Wagner
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1028522359