Neuropharmacology and analgesiaExcitatory drive from the Subthalamic nucleus attenuates GABAergic transmission in the Substantia Nigra pars compacta via endocannabinoids
Introduction
The endocannabinoid (eCB) system comprises of CB1 cannabinoid receptors predominantly located on presynaptic terminals and endogenous ligands (endocannabinoids, eCBs) produced in postsynaptic neurons which, by acting on CB1 receptors, attenuate neurotransmitter release (Kano et al., 2009). Thus, the primary role of eCBs is modulation of synaptic transmission in a retrograde and local fashion. While the eCB system has been the topic of extensive studies since its key components have been discovered in 2001 (Kreitzer and Regehr, 2001, Ohno-Shosaku et al., 2001, Wilson and Nicoll, 2001), this work has been conducted mainly in the hippocampus and cerebellum, with relatively few studies conducted in the basal ganglia, particularly in ventral midbrain which shows high expression of CB1 receptors (Herkenham et al., 1991, Herkenham et al., 1990). The basal ganglia is a network involved in control of a variety of functions including voluntary movement and learning, modulated by dopamine-producing neurons of the Substantia Nigra pars compacta (SNc). Despite the rich expression of CB1 the role of eCBs in this brain region has received little attention (Wallmichrath and Szabo, 2002).
We have recently shown that GABAergic transmission from the Substantia Nigra pars reticulata (SNr; a major output nucleus of the basal ganglia) onto SNc dopaminergic neurons is attenuated by eCBs, and that this modulation is initiated by glutamate (Freestone et al., 2014). However, the source of this glutamatergic input has not been identified. The Subthalamic nucleus (STN) has significant glutamatergic projections to the ventral midbrain, including nigral dopaminergic neurons (Watabe-Uchida et al., 2012), and we now hypothesize that this nucleus is a source of glutamate driving the eCB modulation that we have observed. The STN is part of the classic ‘indirect’ pathway of the basal ganglia, relaying motor commands from the motor cortex-striatum-external Globus Pallidus circuit (Gerfen and Surmeier, 2011). In addition, STN forms a part of the ‘hyperdirect pathway’ relaying information directly from the cortex to SNr neurons (Bosch et al., 2012, Nambu et al., 2002). The present study, conducted in acute rat brain slices, investigated the role of the STN neurons in the eCB-mediated modulation of GABAergic transmission from the SNr to SNc.
Section snippets
Animal handling and acute slice preparation
All procedures were approved by the animals ethics committee of the University of Auckland and in accordance with New Zealand Government Animal Welfare Act. Brain slices were prepared from Wistar rats (P15-19) as described elsewhere (Freestone et al., 2009, Freestone et al., 2014). Briefly, brains were quickly removed from anaesthetized rats and placed in carbogen (95% O2/5% CO2)-bubbled chilled artificial cerebrospinal fluid (ACSF) containing (mM): NaCl 126, NaHCO3 24, glucose 10, KCl 2.5, CaCl
Results
Whole-cell current and voltage clamp recordings were made from 76 dopaminergic SNc neurons (Rm 126±5 MΩ, Cm 105±5 pF, Vm −56.4.±0.8 mV) which had relatively large and multipolar cell bodies (20–30 µm) and fired action potentials at low frequency (1.4±0.2 Hz). To confirm correct placement of the stimulating electrode in the STN, additional whole-cell recordings were made from STN neurons which showed properties consistent with those described in previous studies (Gajendiran et al., 2005, Nakanishi et
Discussion
We investigated the role of the STN in modulating synaptic transmission in downstream dopaminergic neurons in the SNc. Our results show that electrical stimulation of glutamatergic STN neurons reduced GABAergic transmission from SNr neurons to dopaminergic SNc neurons and that this effect is mediated by eCBs. The degree of GABAergic attenuation was proportional to the extent of STN activation. In addition, STN neurons were also stimulated using local U-tube application of muscarinic
Acknowledgments
This study was supported by the Auckland Medical Research Foundation (to PF) and Aotearoa Foundation Centre for Brain Research Fellowship (to PF).
References (51)
- et al.
The functional anatomy of basal ganglia disorders
Trends Neurosci.
(1989) - et al.
Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice
Neuroscience
(2012) - et al.
Drug-dependent ion channel gating by application of concentration jumps using U-tube technique
Methods Enzymol.
(1999) - et al.
The ultrastructural morphology of the subthalamic-nigral axon terminals intracellularly labeled with horseradish peroxidase
Brain Res.
(1984) - et al.
Synaptic localization of ionotropic glutamate receptors in the rat substantia nigra
Neuroscience
(2000) - et al.
M3 muscarinic receptors mediate cholinergic excitation of the spontaneous activity of subthalamic neurons in the rat
Neurosci. Lett.
(1996) - et al.
Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.
Neuropharmacology
(2014) - et al.
Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta
Neurosci. Res.
(1995) - et al.
Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons
Eur. J. Pharmacol.
(1979) - et al.
Branched output neurons of the rat subthalamic nucleus: electrophysiological study of the synaptic effects on identified cells in the two main target nuclei, the entopeduncular nucleus and the substantia Nigra
Neuroscience
(1983)
Neuronal localization of cannabinoid receptors in the basal ganglia of the rat
Brain Res.
Pedunculopontine tegmental nucleus neurons provide reward, sensorimotor, and alerting signals to midbrain dopamine neurons
Neuroscience
The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine
Prostaglandins Leukotrienes Essent. Fatty Acids
Basal ganglia and processing of cortical information: functional interactions between trans-striatal and trans-subthalamic circuits in the substantia nigra pars reticulata
Neuroscience
Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto purkinje cells
Neuron
A continuous high frequency stimulation of the subthalamic nucleus determines a suppression of excitatory synaptic transmission in nigral dopaminergic neurons recorded in vitro
Exp. Neurol.
Electrical membrane properties of rat subthalamic neurons in an in vitro slice preparation
Brain Res.
Functional significance of the cortico–subthalamo–pallidal ‘hyperdirect’ pathway
Neurosci. Res.
Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals
Neuron
Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data
Brain Res.
Activation of subthalamic neurons produces NMDA receptor-mediated dendritic dopamine release in substantia nigra pars reticulata: a microdialysis study in the rat
Brain Res.
Cannabinoids inhibit striatonigral GABAergic neurotransmission in the mouse
Neuroscience
Whole-brain mapping of direct inputs to midbrain dopamine neurons
Neuron
An update on the connections of the ventral mesencephalic dopaminergic complex
Neuroscience
Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation.
J. Neurosci.
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Mechanisms of endocannabinoid control of synaptic plasticity
2021, NeuropharmacologyCitation Excerpt :It should be noted that the relative role of the postsynaptic group 1 receptor subtypes, mGluR1 and mGluR5, in retrograde eCB signalling varies throughout the brain. In addition to this, agonist induced activation of postsynaptic M1/M3 Gαq/11-coupled mAChRs has also been shown to induced retrograde eCB inhibition of synaptic transmission in several brain regions (Edwards et al., 2006; Freestone et al., 2015; Fukudome et al., 2004; Lau and Vaughan, 2008; Martin et al., 2015; Narushima et al., 2006; Neuhofer et al., 2018). Activation of the retrograde eCB signalling system is not exclusive to metabotropic glutamate and cholinergic receptors.