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Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of neurons in the substantia nigra that project to the striatum and release dopamine (DA), which is required for normal movement. Common non-motor symptoms likely involve abnormalities with other neurotransmitters, such as serotonin, norepinephrine, acetylcholine, glycine, glutamate and gamma-aminobutyric acid (GABA). As part of a broad effort to provide better PD research tools, the Michael J. Fox Foundation for Parkinson's Research funded the generation and characterization of knockout (KO) rats for genes with PD-linked mutations, including PINK1, Parkin, DJ-1 and LRRK2. Here we extend the phenotypic characterization of these lines of KO rats to include in vivo microdialysis to measure both basal and potassium-induced release of the above neurotransmitters and their metabolites in the striatum of awake and freely moving rats at ages 4, 8 and 12 months compared to wild-type (WT) rats. We found age-dependent abnormalities in basal DA, glutamate and acetylcholine in PINK1 KO rats and age-dependent abnormalities in basal DA metabolites in Parkin and LRRK2 KO rats. Parkin KO rats had increased glycine release while DJ-1 KO rats had decreased glutamate release and increased acetylcholine release compared to WT rats. All lines except DJ-1 KO rats showed age-dependent changes in release of one or more neurotransmitters. Our data suggest these rats may be useful for studies of PD-related synaptic dysfunction and neurotransmitter dynamics as well as studies of the normal and pathogenic functions of these genes with PD-linked mutations.

Receptor-associated protein appears to play an important role in low-density lipoprotein receptor-related protein trafficking. Since ligands for the low-density lipoprotein receptor-related protein have been implicated in Alzheimer's disease and normal functioning of this protein is indispensable for central nervous system development, deficient receptor-associated protein expression may result in central nervous system alterations. In this study, receptor-associated protein knockout mice were behaviorally tested and nervous system integrity was assessed via in situ hybridization and immunocytochemical/laser confocal microscopy methods. Receptor-associated protein knockout mice were found to be cognitively impaired in the Morris water maze compared to controls. In wild-type mice, the receptor-associated protein was found to be highly co-expressed with somatostatin in hippocampal and neocortical inhibitory neurons. Receptor-associated protein knockout mice, however, showed a significant decrease in number of somatostatin-expressing neurons of the CA1 region and somatostatin expression within these neurons. The decreased number of somatostatin neurons significantly correlated with cognitive impairment observed in the receptor-associated protein knockout mice. These results suggest a novel role for receptor-associated protein in modulating the functioning of somatostatin-producing neurons. Furthermore, this has implications for Alzheimer's disease pathogenesis, in which altered regulation of both somatostatin and the known low-density lipoprotein receptor-related protein ligands are a consistent finding.