Gap junction blockers attenuate beta oscillations and improve forelimb function in hemiparkinsonian rats

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by akinesia, bradykinesia, resting tremors and postural instability. Although various models have been developed to explain basal ganglia (BG) pathophysiology in PD, the recent reports that dominant beta (β) oscillations (12–30Hz) in BG nuclei of PD patients and parkinsonian animals coincide with motor dysfunction has led to an emerging idea that these oscillations may be a characteristic of PD. Due to the recent realization of these oscillations, the cellular and network mechanism(s) that underlie this process remain ill-defined. Here, we postulate that gap junctions (GJs) can contribute to β oscillations in the BG of hemiparkinsonian rats and inhibiting their activity will disrupt neuronal synchrony, diminish these oscillations and improve motor function. To test this, we injected the GJ blockers carbenoxolone (CBX) or octanol in the right globus pallidus externa (GPe) of anesthetized hemiparkinsonian rats and noted whether subsequent changes in β oscillatory activity occurred using in vivo electrophysiology. We found that systemic treatment of 200mg/kg CBX attenuated normalized GPe β oscillatory activity from 6.10±1.29 arbitrary units (A.U.) (pre-CBX) to 2.48±0.87 A.U. (post-CBX) with maximal attenuation occurring 90.0±20.5min after injection. The systemic treatment of octanol (350mg/kg) also decreased β oscillatory activity in a similar manner to CBX treatment with β oscillatory activity decreasing from 3.58±0.89 (pre-octanol) to 2.57±1.08 after octanol injection. Next, 1μl CBX (200mg/kg) was directly injected into the GPe of anesthetized hemiparkinsonian rats; 59.2±19.0min after injection, β oscillations in this BG nucleus decreased from 3.62±1.17 A.U. to 1.67±0.62 A.U. Interestingly, we were able to elicit β oscillations in the GPe of naive non-parkinsonian rats by increasing GJ activity with 1μl trimethylamine (TMA, 500nM). Finally, we systemically injected CBX (200mg/kg) into hemiparkinsonian rats which attenuated dominant β oscillations in the right GPe and also improved left forepaw akinesia in the step test. Conversely, direct injection of TMA into the right GPe of naive rats induced contralateral left forelimb akinesia. Overall, our results suggest that GJs contribute to β oscillations in the GPe of hemiparkinsonian rats.