Deep brain stimulation of the subthalamic nucleus preferentially alters the translational profile of striatopallidal neurons in an animal model of Parkinson's disease.

Naomi P Visanji,Iman Kamali Sarvestani,Lili-Naz Hazrati,Meaghan C Creed,Clement Hamani,Zahra Shams Shoaei,Josã© N Nobrega

doi:10.3389/fncel.2015.00221

Abstract

Deep brain stimulation targeting the subthalamic nucleus (STN-DBS) is an effective surgical treatment for the motor symptoms of Parkinson's disease (PD), the precise neuronal mechanisms of which both at molecular and network levels remain a topic of debate. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively identify changes in translational gene expression in either Drd1a-expressing striatonigral or Drd2-expressing striatopallidal medium spiny neurons (MSNs) of the striatum following STN-DBS. 6-hydroxydopamine lesioned mice received either 5 days stimulation via a DBS electrode implanted in the ipsilateral STN or 5 days sham treatment (no stimulation). Striatal polyribosomal RNA was selectively purified from either Drd2 or Drd1a MSNs using the TRAP method and gene expression profiling performed. We identified eight significantly altered genes in Drd2 MSNs (Vps33b, Ppp1r3c, Mapk4, Sorcs2, Neto1, Abca1, Penk1, and Gapdh) and two overlapping genes in Drd1a MSNs (Penk1 and Ppp1r3c) implicated in the molecular mechanisms of STN-DBS. A detailed functional analysis, using a further 728 probes implicated in STN-DBS, suggested an increased ability to receive excitation (mediated by increased dendritic spines, increased calcium influx and enhanced excitatory post synaptic potentials) accompanied by processes that would hamper the initiation of action potentials, transport of neurotransmitters from soma to axon terminals and vesicular release in Drd2-expressing MSNs. Finally, changes in expression of several genes involved in apoptosis as well as cholesterol and fatty acid metabolism were also identified. This increased understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies for PD.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by bradykinesia, akinesia, rigidity, and tremor at rest (Lang and Lozano, 1998)
Our observations suggest that, by various mechanisms discussed in details below, following STN-DBS the indirect pathway is capable of receiving an enhanced input; concurrent alterations are apparent that would dampen the output of these Drd2 medium spiny neurons (MSNs)
Striatal genes whose expression changes following L-DOPA administration (Visanji et al, 2012; Heiman et al, 2014) have a very slim overlap with the striatal genes whose expression changes following STN-DBS. This may suggest that mechanisms controlling therapeutic effect of STNDBS may be very different from those causing the pathology of PD

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by bradykinesia, akinesia, rigidity, and tremor at rest (Lang and Lozano, 1998). The classical model of PD pathophysiology exploits the opposing effects of dopamine on striatopallidal (Drd2) and striatonigral (Drd1a) medium spiny neurons (MSNs) to explain the clinical features of bradykinesia, rigidity, and akinesia (Albin et al, 1989). This model suggests that the loss of striatal dopamine causes an imbalance between the activity of Drd1a and Drd populations leading to abnormal activity in recipient neurons in the pallidum and substantia nigra pars reticulata (SNr) leading to abnormal activity in downstream thalamo-cortico-thalamic activity. A better understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies able to selectively reduce the motor symptoms of PD

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Discussion

Conclusion