PRJNA550435
Transcriptional responses to reduced dopamine in pre- and post-synaptic dopaminergic brain regions in a mouse Tyrosine hydroxylase KO model of Parkinson's Disease
Parkinson's Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by a decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that causes a selective depletion of striatal dopamine without affecting DA neuron survival, by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter expressing neurons. We analyzed transcriptome responses to decreased DA in both pre- and post-synaptic dopaminergic brain regions of DAT:TH KO animals. None of the post-synaptic regions analyzed, Dorsal Striatum, Ventral Striatum and Prefrontal Cortex, shows an overall change in transcriptome as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression of Nr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice. Unexpectedly, we find that half of DAT:TH KO animals show near-normal levels of Th transcription, and also display an overall transcript expression pattern more similar to wild type animals than to the remaining DAT:TH KO mice. These animals could represent recruitment of a pathway attempting to compensate for dopamine loss.