Altered pallido‐pallidal synaptic transmission leads to aberrant firing of globus pallidus neurons in a rat model of Parkinson's disease

Abstract

Key points• We used optogenetics approach to characterize the short-term plasticity of striato-pallidal (STR-GP) and pallido-pallidal (GP-GP) GABAergic synapses in rat brain slices.• We show that only GP-GP (and not STR-GP) transmission is augmented by chronic dopamine depletion.• Finally, we report that altered GP-GP synaptic transmission promotes neuronal synchronization and rebound bursting in globus pallidus neurons.• Our results support the conclusion that maladaptive GP-GP GABAergic transmission is likely to be a key underlying factor of the pathological activity in the globus pallidus observed in Parkinson's disease. AbstractThe pattern of activity of globus pallidus (GP) neurons is tightly regulated by GABAergic inhibition. In addition to extrinsic inputs from the striatum (STR-GP) the other source of GABA to GP neurons arises from intrinsic intranuclear axon collaterals (GP-GP). While the contribution of striatal inputs has been studied, notably its hyperactivity in Parkinson's disease (PD), the properties and function of intranuclear inhibition remain poorly understood. Our objective was therefore to test the impact of chronic dopamine depletion on pallido-pallidal transmission. Using patch-clamp whole-cell recordings in rat brain slices, we combined electrical and optogenetic stimulations with pharmacology to differentiate basic synaptic properties of STR-GP and GP-GP GABAergic synapses. GP-GP synapses were characterized by activity-dependent depression and insensitivity to the D 2 receptor specific agonist quinpirole and STR-GP synapses by frequency-dependent facilitation and quinpirole modulation. Chronic dopamine deprivation obtained in 6-OHDA lesioned animals boosted the amplitude of GP-GP IPSCs but did not modify STR-GP transmission and increased the amplitude of miniature IPSCs. Replacement of calcium by strontium confirmed that the quantal amplitude was increased at GP-GP synapses. Finally, we demonstrated that boosted GP-GP transmission promotes resetting of autonomous activity and rebound-burst firing after dopamine depletion. These results suggest that GP-GP synaptic transmission (but not STR-GP) is augmented by chronic dopamine depletion which could contribute to the aberrant GP neuronal activity observed in PD.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Finally, a highly important parkinsonismrelated change in spontaneous discharge is the abnormal level of synchrony between neighboring neurons [144,152]. It is not specifically known how changes such as burst discharges, oscillatory discharge, or abnormal synchrony develop in parkinsonism, although altered striatal output to the extrastriatal basal ganglia, changes in collateral inhibition in the external pallidum [156], or changes in the strength and morphology of synapses within the subthalamopallidal network of connections (see below and [157,158]) may contribute to correlated oscillatory activity in the output nuclei of the basal ganglia [152,159,160] .…”

“…In contrast, interventions directed at the PPN have revealed significant motoric effects in animal experiments [55]. Thus, PPN inactivation in normal primates reduces body movements of arms, trunk, and legs [142][143][144][145][146], and PPN injection of a GABA-A receptor antagonist, or low-frequency stimulation of PPN, alleviates experimental akinesia in monkeys, presumably by increasing PPN activity [146][147][148][149][150][151][152][153][154][155][156]. This constellation of findings suggests the possibility that the descending basal ganglia projections to the brainstem may play a greater role in the pathophysiology of akinesia/bradykinesia and movement than is commonly assumed.…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…Many of them assume or report a difference in connectivity within the basal ganglia (e. g., Terman et al [2002], Miguelez et al [2012], Fan et al [2013], Gittis et al [2011]) or from cortex to the basal ganglia [Magill et al, 2001, Deffains and Bergman, 2015, Mathai et al, 2015, DeLong and Wichmann, 2015, Chu et al, 2015. It is unclear what connectivity changes are pathological, adaptive, maladaptive or epiphenomenological, and which connectivity changes occur only in animal models but not in patients.…”

“…Synaptic coupling inside the GPe via local axon collaterals is well established [Francois et al, 1984, Kita, 1994, Sadek et al, 2007, Miguelez et al, 2012 although functional GPe connectivity is highly variable and depends on the brain state [Magill et al, 2006]. Rat GP-GP synapses have considerably different properties than striatum-GP synapses, with a lower paired-pulse ratio and weak responses to stimulation [Sims et al, 2008].…”

“…A recent study demonstrates that rat GP-GP connections are also highly efficacious in modulating postsynaptic activity despite substantial short time depression and sparse connectivity [Bugaysen et al, 2013]. Miguelez et al [2012] showed that GP-GP inhibitory synaptic transmission increased in a rat 6-OHDA model, leading to enhanced rebound bursting. This altered transition may have major impacts on neural dynamics.…”