Abstract
Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2. α-syn overexpression increased phosphorylation of ribosomal protein S6 (p-rpS6) in SNpc neurons, a readout of trkB activation. Rats received intranigral injections of rAAV2/5 α-syn and three weeks later received four weeks of STN DBS or electrode implantation that remained inactive. STN DBS did not protect against α-syn-mediated deficits in forelimb akinesia, striatal denervation or loss of SNpc neuron, nor did STN DBS elevate p-rpS6 levels further. ON stimulation, forelimb asymmetry was exacerbated, indicating α-syn overexpression-mediated neurotransmission deficits. These results demonstrate that STN DBS does not protect the nigrostriatal system against α-syn overexpression-mediated toxicity. Whether STN DBS can be protective in other models of synucleinopathy is unknown.
Highlights
Degeneration as well as after nigrostriatal degeneration onset
We recently demonstrated that modest overexpression of α-syn more closely resembles the transcriptional signature observed in substantia nigra pars compacta (SNpc) neurons in sporadic PD, whereas higher levels of overexpression produce downregulation of multiple trophic signaling models, downregulation that is not observed in sporadic PD34,35
On SNpc TH immunoreactive (THir) neurons all ipsilateral, SNpc THir Active and Inactive counts were combined and compared to all contralateral SNpc THir Active and Inactive counts. With this enhanced statistical power, significantly fewer SNpc THir neurons were detected ipsilateral to rAAV 2/5 α-syn injection compared to the contralateral SNpc (t(11) = 2.106, p = 0.0295), revealing an ≈8% decrease in the ipsilateral SNpc due to α-syn overexpression. These results demonstrate that electrode implantation may increase the variability of α-syn mediated nigral degeneration; comparison of ipsilateral THir SNpc neurons between Active and Inactive rats demonstrates that the modest α-syn-mediated loss of THir neurons in the SNpc is not affected by Subthalamic nucleus deep brain stimulation (STN DBS)
Summary
Evaluation of the neuroprotective potential of STN DBS in non-toxicant-based PD animal models is warranted to allow for more definitive validation Another major limitation of previous STN DBS studies examining neuroprotection against neurotoxicants is that none have observed sparing or reinnervation of striatal dopaminergic terminals[10,11,12,13,14]. One preclinical PD model that has been extensively explored in our laboratory, and in others, is viral vector-mediated nigrostriatal overexpression of wildtype human α-syn[31,32,33] This approach drives elevated α-syn expression levels within the nigrostriatal system resulting in α-syn aggregation, dopaminergic terminal dysfunction and loss, motor impairments and degeneration of SNpc neurons[33].
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