Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABA_Aand GABA_BReceptors

Abstract

Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA A receptor (GABA A R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA A R-and GABA B R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA A Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA B Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA B Rmediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA A Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD.

Origins of GABAA and GABAB Receptor-Mediated Responses of Globus Pallidus Induced after Stimulation of the Putamen in the Monkey

“…that ambient GABA levels in GPe projection sites play a significant role in the control of the rate and pattern generations in neuronal activities (Galvan et al, 2005;Hallworth and Bevan, 2005;Kaneda and Kita, 2005). This observation is consistent with our previous study suggesting that the spontaneous firing of most of GPe neurons in vivo is sufficient to release the GABA required to activate perisynaptic GABA B receptors (Kaneda and Kita, 2005).…”

Enhancement of Excitatory Synaptic Integration by GABAergic Inhibition in the Subthalamic Nucleus

“…These channels underlie a low-threshold Ca 2ϩ spike on which a rebound burst of APs rides in STN and other neurons (Nakanishi et al, 1987;Huguenard, 1996;Beurrier et al, 1999;Song et al, 2000;Hallworth et al, 2003). However, sufficient deinactivation of Ca v 3 channels for the generation of a low-threshold Ca 2ϩ spike requires barrages of summating IPSPs generated at frequencies greater than those studied here (Bevan et al, 2002a;Hallworth and Bevan, 2005).…”

“…During normal movement the cortex, the STN-GP network and basal ganglia output nuclei exhibit coherent activity in the ␥-frequency band (30 -100 Hz), whereas in PD, which is characterized by akinesia, bradykinesia and limb tremor (4 -8 Hz), coherent activity at lower frequencies is more commonly observed (Brown, 2003;Dostrovsky and Bergman, 2004). Rhythmic activity in the tremor frequency band may be generated within the dopamine-depleted STN-GP network (Plenz and Kitai, 1999;Bevan et al, 2002b;Hallworth and Bevan, 2005) through a mechanism similar to the one underlying spindle oscillations in the sensory thalamus (McCormick and Bal, 1997;McCormick, 1999). In addition, cortical ␤ oscillations may be transmitted abnormally to the extrastriatal basal ganglia via the corticosubthalamic pathway, leading to the pathological synchronization of spiking activity (Goldberg et al, 2002(Goldberg et al, , 2004Levy et al, 2002;Williams et al, 2002).…”

Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons

“…However, subsequent application of 100 μM of SNAP failed to inhibit the spontaneous firing of neurons in the presence of bicuculline, suggesting that NO effects are mediated by activation of GABA A receptors. Since the increase in firing frequency after application of bicuculline could be due to its effects on channels regulating spike accommodation, 50 μM of picrotoxin, another GABA A receptor antagonist was also used (Sanhueza and Bacigalupo, 2005;Hallworth and Bevan, 2005). Similar to bicuculline, picrotoxin increased the discharge rate of the dl-PAG neurons (3.85±0.38 to 6.92±0.42 Hz, P<0.05, n=6) and attenuated the effect of SNAP (6.53±0.38 Hz after SNAP, P>0.05, SNAP plus picrotoxin vs. picrotoxin alone, n=6).…”