system
Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Activating Transcription Factor 2, Aging, Animals, Carrier Proteins, Chromatography, High Pressure Liquid, Corpus Striatum, Cyclic Nucleotide Phosphodiesterases, Type 7, Dopamine, Electrophysiology, Homer Scaffolding Proteins, Humans, In Situ Hybridization, Fluorescence, Mice, Mice, Knockout, Mice, Mutant Strains, Neuronal Calcium-Sensor Proteins, Neuronal Plasticity, Neuropeptides, Oligonucleotide Array Sequence Analysis, Radioimmunoprecipitation Assay, Receptor, Cannabinoid, CB1, Reverse Transcriptase Polymerase Chain Reaction, alpha-Synuclein.
user
Does a53T-alpha-synuclein overexpression impair dopamine signaling and striatal synaptic plasticity in old mice? Context: Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice.
assistant
Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches. Final Decision: yes