gms | German Medical Science

Objective: Modulation of metabotropic glutamate receptors (mGluRs) has evolved a therapeutic target for Parkinson’s disease (PD), both in alleviating PD symptoms and in slowing disease progression. MGluRs modulate synaptic transmission throughout the basal ganglia, and it is assumed that nigral neuroprotection can be effected through a reduction of glutamatergic tone. Chronic High Frequency Stimulation (HFS) of deep brain structures has been shown to strongly modulate glutamatergic transmission within the basal ganglia circuit. Here, the impact of DBS on the expression of mGluRs was analyzed in the rat.

Method: 6-OHDA lesioned rats (male Wistar, age 21 days, weighing ~300 g) received HFS or sham stimulation in the STN using an implantable microstimulation system. Group size was 5 animals each. STN-HFS was initiated 5 days after the intrastriatal 6-OHDA lesion and continuous (current intensity 50 or 100 µA, frequency 131 Hz, pulse width 52 µs. After 14 days of stimulation animals were sacrificed by decapitation and brains were shock frozen in nitrogene cooled methylbutane. Striata and frontal cortices were dissected with the aid of Paxinos and Watson’s rat brain atlas, using a cryostate. Levels of mGluR subtypes 1-8 were analyzed in homogenates of striatal and cortical tissue by quantitative PCR.

Results: PCR revealed a significant up-regulatory effect of HFS on mGluR4 and mGluR6 in all animals, both in striatal and cortical tissues. Relative quantification (RQ) values of mRNA in stimulated animals as compared to placebo were: mGluR1 cortex: 1.4; mGluR1 striatum: 1.7; mGluR3 cortex: 0.8; mGluR3 striatum: 1.4; mGluR4 cortex: 3.5; mGluR4 striatum: 4.5; mGluR5 cortex: 1.0; mGluR5 striatum: 1.7; mGluR6 cortex: 3.8; mGluR6 striatum: 4.5; mGluR7 cortex: 0.4; mGluR7 striatum: 1.0. Bilateral effects were observed despite unilateral stimulation. A placement effect was observed.

Conclusions: Class III mGluRs type 4 and 6, which have previously been shown to exert dopamine-like effects and reduce glutamatergic tone, are modulated positively by HFS. Our results suggest that the upregulation of mGluR4 and 6 after HF may participate in both the symptomatic relief as in the long-term neuroprotective effect of this therapy.