Mechanism of parkinsonian neuronal oscillations in the primate basal ganglia: some considerations based on our recent work

Abstract

Accumulating evidence suggests that abnormal neuronal oscillations in the basal ganglia (BG) contribute to the manifestation of parkinsonian symptoms. In this article, we would like to summarize our recent work on the mechanism underlying abnormal oscillations in the parkinsonian state and discuss its significance in pathophysiology of Parkinson's disease. We recorded neuronal activity in the BG of parkinsonian monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Systemic administration of L-DOPA alleviated parkinsonian motor signs and decreased abnormal neuronal oscillations (8-15 Hz) in the internal (GPi) and external (GPe) segments of the globus pallidus and the subthalamic nucleus (STN). Inactivation of the STN by muscimol (GABAA receptor agonist) injection also ameliorated parkinsonian signs and suppressed GPi oscillations. The blockade of glutamatergic inputs to the STN by local microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (glutamatergic NMDA receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (glutamatergic AMPA/kainate receptor antagonist) suppressed neuronal oscillations in the STN. STN oscillations were also attenuated by the blockade of GABAergic neurotransmission from the GPe to the STN by muscimol inactivation of the GPe. These results suggest that cortical glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of GPe and STN neurons in the parkinsonian state. The oscillatory activity in the STN is subsequently transmitted to the GPi and may contribute to manifestation of parkinsonian symptoms.

Keywords: Parkinson’s disease; basal ganglia; globus pallidus; monkey; neuronal oscillation; subthalamic nucleus; β-band.

Figure 1

Effects of subthalamic nucleus (STN) inactivation on neuronal activity of the internal segment of the globus pallidus (GPi) under the parkinsonian state. (A) A schematic diagram showing anatomical connections of the basal ganglia and the experimental method. Recording from GPi neurons was performed with muscimol injection into the STN to block STN inputs to the GPi. Open and filled arrows represent glutamatergic and GABAergic projections, respectively. Cx, cerebral cortex; GPe, external segment of the globus pallidus; Str, striatum; Th, thalamus. (B) A representative GPi neuron showing abnormal oscillations in the parkinsonian state. (1) Autocorrelograms calculated from a 50-s spike train and (2) power spectra of the same spike trains are shown. Gray dashed lines represent a confidence level of P = 0.01. (C) Muscimol inactivation of the STN decreased the firing rate and 8–15 Hz oscillatory activity of the GPi neuron. Modified from Tachibana et al. (2011).

Figure 2

Effects of the blockade of ionotropic glutamatergic inputs to STN neurons under the parkinsonian state. (A) Recording from STN neurons was performed with intrasubthalamic microinjection of CPP and NBQX to block glutamatergic inputs to the STN. (B) A representative STN neuron showing abnormal oscillatory activity under the parkinsonian state. (C) Intrasubthalamic microinjection of CPP and NBQX decreased 3–8 Hz and 8–15 Hz oscillations of the STN neuron. Modified from Tachibana et al. (2011).

Figure 3

Effects of GPe inactivation on STN neurons under the parkinsonian state. (A) Recording from STN neurons was performed with muscimol injection into the GPe to block GABAergic inputs from the GPe. (B) A representative STN neuron showing abnormal 8–15 Hz oscillations under the parkinsonian state. (C) Muscimol inactivation of the GPe decreased the 8–15 Hz oscillations and increased the firing rate of the STN neuron. Modified from Tachibana et al. (2011).

Figure 4

Schematic diagram showing neural circuits involved in the generation of BG oscillations. Under the parkinsonian sate, glutamatergic inputs from the Cx (and also from the Th) to the STN and reciprocal GPe-STN interconnections can cooperatively generate and amplify the oscillatory activity of STN and GPe neurons. Such oscillatory activity is subsequently transmitted to the GPi, contributing to the expression of parkinsonian symptoms. Open and filled circles represent glutamatergic and GABAergic synapses, respectively. Modified from Tachibana et al. (2011).