What neurodegenerative disease is associated with a loss of dopamine neurons that project to the basal ganglia?

The Journal of Physiological Sciences volume 66, pages 435–446 [2016]Cite this article

• 18k Accesses

• 12 Citations

• 10 Altmetric

• Metrics details

Abstract

The authors have reviewed recent research advances in basal ganglia circuitry and function, as well as in related disorders from multidisciplinary perspectives derived from the results of morphological, electrophysiological, behavioral, biochemical and molecular biological studies. Based on their expertise in their respective fields, as denoted in the text, the authors discuss five distinct research topics, as follows: [1] area-specific dopamine receptor expression of astrocytes in basal ganglia, [2] the role of physiologically released dopamine in the striatum, [3] control of behavioral flexibility by striatal cholinergic interneurons, [4] regulation of phosphorylation states of DARPP-32 by protein phosphatases and [5] physiological perspective on deep brain stimulation with optogenetics and closed-loop control for ameliorating parkinsonism.

Introduction

Basal ganglia [BG] are a complex network of nuclei in the forebrain which play critical roles in motor control. It has been suggested that any damage to/disorganization of the BG may be closely related to various neurodegenerative diseases, such as Parkinson’s disease [PD] [1]. The roles of BG can be envisioned those of processing information streams through several neuronal circuits composed of a variety of neurons as well as glial cells [2]. Although the profiles of these neurons have been clarified [3], detailed knowledge of the transmitters, modulators and the respective receptors involved in these functional circuits is currently limited.

Dopamine [DA] is one of the critical neurotransmitters and/or neuromodulators in BG circuitries, affecting the control of motor activity and emotion as well as abuses of addictive drugs [4]. Dopaminergic neurons in the substantia nigra pars compacta project their axons towards medium spiny neurons and cholinergic interneurons in the striatum [5, 6], thereby regulating the neuronal activities of these striatal neurons. The nigro-striatal dopaminergic pathway has important functions in motor control [7] through the interaction DA and acetylcholine [ACh] [8, 9]. Although recent molecular biological, biochemical, pharmacological and electrophysiological studies have revealed the profiles of DA receptors [10], little information is yet available on the mechanisms of DA release, action of physiologically released DA or the regulatory roles of these receptors in brain functions.

In this review, recent findings on the BG circuitry and function are presented and discussed by experts in the field of BG research, based on studies which used refined tools for morphology, electrophysiology, biochemistry and molecular biology. These findings may provide a clue to the understanding of new aspects of BG functions, opening the doors to new strategies for the therapeutics of BG-related disorders.

Area-specific DA receptor expression of astrocytes in basal ganglia [Katsuya Yamada]

The substantia nigra pars reticulata [SNr], a nucleus located in the midbrain and a major output nucleus of the basal ganglia, consists mostly of gamma-aminobutyric acid-ergic [GABAergic] neurons. These SNr GABAergic neurons receive inputs from the striatum and project their axons to remote nuclei, such as the superior colliculus, thalamus and pedunculopontine nucleus of the brain stem [Fig. 1]. One of the physiological roles of SNr is to regulate motor activity depending upon information processed in the striatum [11]. The SNr may also act as a sensor of hypoxic/hypoglycemic conditions [12–14].

Fig. 1

Schematic diagram of information flow through striatonigral axis. SNr Substantia nigra pars reticulata, SNc substantia nigra pars compacta, SC superior colliculus, PPN pedunculopontine nucleus

Full size image

The nucleus adjacent to the SNr is the substantia nigra pars compacta [SNc], consisting mainly of dopaminergic neurons. It is the selective loss of SNc neurons which is a major cause of Parkinson’s disease. Interestingly, it has been well established that SNc dopaminergic neurons release dopamine from their dendrite which extends deeply into the SNr [dendritic release] [15]. SNr cells targeted by the dendritically released dopamine are not yet fully understood and unlike axonal release, non-synaptic release from the dendrites makes it difficult to identify the target cells.

SNr GABAergic neurons show high-frequency spontaneous firings that can be recorded in acute slices and even in acutely dissociated neurons, providing valuable information [12–14]. Based on our own experience using such acute slices and single cells in SNr, it seems unlikely that dopamine directly affects SNr GABAergic neuron firing.

Immunohistochemistry studies have shown that SNr mainly expresses DA D1 receptors [D1R], whereas SNc abundantly expresses dopamine D2 receptors [D2R] [16]. Thus, the cells being targeted by the dendritically released dopamine may well express D1R. Although it is widely accepted that D1R is functionally expressed on the striatonigral axons [17], the very dense immunoreactivity pattern for D1R in the SNr led us to explore whether cellular components other than neurons are involved in the expression as well. However, due to extremely fine D1R immunoreactivity in the SNr, our initial confocal microscopic examination of SNr slices using antibodies, such as against D1R/Parvalbumin, D1R/tyrosine hydroxylase, D1R/glial fibrillary acidic protein and D1R/3-phospho-d-glycerate dehydrogenase, did not provide conclusive evidence of the involvement of other cellular components. Alternatively, Katsuhiro Nagatomo from our laboratory has successfully utilized D1R promoter-controlled yellow fluorescent protein-expressing transgenic mouse provided by Prof. Kazuto Kobayashi to identify the cellular component expressing D1R. Combined with information obtained from double immunocytochemistry studies, we also confirmed that the heterogeneous D1R expression in astrocytes is not restricted to the SNr but also appears more widely in the BG.

In PD patients, a decrease in the number of SNc neuron dendrites might well reduce dopamine-mediated, non-striatonigral regulation of SNr function related to motor movement and/or sensing energy status. It may be of interest to investigate how the dendritically released dopamine influences neurons/glia interplay in the SNr circuitry.

The role of physiologically released DA in the striatum [Toshihiko Momiyama]

One of the potential neurophysiological events contributing to the BG-related motor control is synaptic transmission in the striatum [18]. In cholinergic interneurons, activation of postsynaptic D1-like receptors depolarizes the membrane by closing potassium channels or opening non-selective cation channels [19], whereas activation of presynaptic D2-like receptors located on GABAergic terminals inhibits GABA release onto cholinergic interneurons [20, 21] by selectively blocking N-type calcium channels [21], as depicted schematically in Fig. 2. However, the role of physiologically released DA as well as the physiological linkage between DA receptors and calcium channels remain unknown.

Fig. 2

Schematic drawings of a gamma-aminobutyric acid-ergic [GABAergic] synapse onto a striatal cholinergic interneuron in wild type and dopamine D2 receptor knockout [D2R KO] mice summarizing current data. Left Hypothesized localization of N- and P/Q-type calcium channels as well as of D2R in wild-type mice. Pharmacological results using selective blockers suggest the possibility that P/Q-type calcium channels are localized more closely to the release site than N-type calcium channels, which are coupled to D2R. The bar below GABA A R on the postsynaptic membrane represents the inhibitory effect, with the width corresponding to the magnitude of inhibition. Right In D2R KO mice, deletion of D2R results in a reduced contribution of N-type calcium channels and an increased contribution of P/Q-type calcium channels. Note the smaller size of the N-type calcium channels in D2R KO mice in the schema and the larger size of the P/Q-type calcium channels, compared with those in wild-type mice. Additional unknown factors should mediate the change in total neuronal activity of cholinergic interneurons

Full size image

In this section, recent findings using the D2R-knockout [D2R-KO] mice are reviewed, showing [1] the effect of stimulus frequency on GABAergic transmission on striatal cholinergic interneurons and on their spontaneous firing in order to determine the physiological role of endogenously released DA and [2] the physiological linkage between dopamine D2R and N-type calcium channels in the modulation of GABA release.

Frequency-dependent suppression of inhibitory postsynaptic current amplitude

Inhibitory postsynaptic currents [IPSCs] evoked in striatal cholinergic interneurons have been shown to be presynaptically inhibited by bath application of DA or D2-like receptor agonists [21, 22]. However, the modulatory roles of physiologically released DA in the striatum remain unknown. To address the question, we examined the dependency of the evoked IPSCs on stimulus frequency between 0.2 and 10 Hz. IPSCs evoked in striatal cholinergic interneurons of wild-type mice showed frequency-dependent suppression during sustained stimulation. To clarify the receptors involved in this frequency-dependent suppression of IPSCs, we then examined the effect of sulpiride, a D2-like receptor antagonist, on the frequency-dependent inhibition of IPSCs in wild-type mice. There was a significant difference [P  0.05] from that of those in wild-type mice. In D2R-KO mice, stimulation with 5 and 10 Hz had no significant [P > 0.05] effect on the firing rate.

Calcium channel subtypes involved in the transmission

Based on the findings of selective coupling between D2-like receptors and N-type calcium channels observed in rats or wild-type mice [21, 22], we examined the effect of D2R deletion on the contribution of calcium channel subtypes to the GABAergic transmission onto striatal cholinergic interneurons using D2R-KO mice. The inhibitory effect of ω-conotoxin [ω-CgTX] on the IPSCs in D2R-KO mice was significantly [P