Pallidal gap junctions‐triggers of synchrony in Parkinson's disease?

Abstract

Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin-36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin-36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin-36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin-36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia.

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

“…Yet, increased abundance of GJs could also contribute to β oscillations since 43% more Cx36 was reported in the GPe of PD patients than matched controls (Schwab et al, 2014). The GPi also had marked increases in Cx36, but none were observed in the STN (Schwab et al, 2014). In the future, we could directly inject TMA into the right GPe of hemiparkinsonian rats to see if further increase in dominant β oscillatory activity was observed.…”

“…Since a lack of dopamine has been shown to increase GJ activity in cells in other BG nuclei (Cepeda et al, 1989;Grace, 1994, 1999) and PD patients can lose 82% of dopamine in the GPe (Rajput et al, 2008), we speculate that this could underlie the emergence of β oscillatory activity in PD. Yet, increased abundance of GJs could also contribute to β oscillations since 43% more Cx36 was reported in the GPe of PD patients than matched controls (Schwab et al, 2014). The GPi also had marked increases in Cx36, but none were observed in the STN (Schwab et al, 2014).…”

“…In addition, GPe neurons spike in the β frequency (Johnson et al, 2009), synchronize with each other at this frequency range many distances away in parkinsonian animals (Mitelman et al, 2011) and rat GPe express GJ subunits such as connexin (Cx) 32 (Dermietzel et al, 1989;Vis et al, 1998) and Cx36 (Rash et al, 2000), which are present in neurons in other brain regions (Colwell, 2000;Li et al, 2001;Oguro et al, 2001;Priest et al, 2001;Solomon et al, 2001). Lastly, Cx36 subunit immunoreactivity in the GPe is higher in PD patients than control brains (Schwab et al, 2014).…”

“…GJs can synchronize neuronal activity in the hippocampus (Draguhn et al, 1998;Traub et al, 2000) and neocortex (Beierlein et al, 2000) to produce neuronal oscillations and they are involved in β oscillations in the rat somatosensory cortex in vitro (Roopun et al, 2006). Lastly, a loss of dopamine in parkinsonian animals coincides with increased GJ activity (Cepeda et al, 1989;Grace, 1994, 1999) and it was recently reported that PD patients have higher expression levels of GJs in the BG (Schwab et al, 2014).…”

A Pooling Genome-Wide Association Study Combining a Pathway Analysis for Typical Sporadic Parkinson’s Disease in the Han Population of Chinese Mainland

“…Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in sPD, gap junctions could play a major role in modifying this synchrony because they show functional plasticity under the influence of dopamine and after neural injury. Gap junctions act as a powerful modulator of synchrony in the basal ganglia [56]. Each neurobiological molecule of gap junction pathway gained from our study is shown in Table 2, which showed that the partial loci and/or genes in the embryonic development, the electrical coupling, the metabolic transport, apoptosis, the maintaining cellular homeostasis, and growth control participated in the pathogenesis of sPD, which could be associated with the generation of alpha-synuclein.…”