Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

doi:10.1016/j.neuroscience.2011.12.027

Neuroscience

Volume 203, 17 February 2012, Pages 1-11

https://doi.org/10.1016/j.neuroscience.2011.12.027 Get rights and content

Abstract

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Highlights

▶We have studied synaptic plasticity of the cortico-subthalamic pathway. ▶We find HFS depresses cortico-subthalamic synapses but only in dopamine-depleted tissue. ▶LFS enhances transmission but only in dopamine-intact tissue. ▶Both these plasticity have presynaptic components. ▶Suggests dopamine-dependent changes in the synaptic weight of this pathway. ▶Suggests DBS promotes synaptic depression in Parkinson's disease.

Section snippets

Experimental procedures

All the animals in this study were used in accordance with the Animals (Scientific Procedures) Act, 1986 (UK) and the European Communities Council Directive (80/609/EEC).

Results

In the presence of picrotoxin (50 μM), stimulation within the internal capsule elicited a short-latency (monosynaptic) inward current that reversed around 0 mV and was blocked by glutamate receptor antagonists CNQX (10 μM) and d-AP5 (50 μM). At a stimulation frequency of 0.1 Hz, no potentiation or rundown of these synaptic responses and no changes in intrinsic properties such as resting membrane potential (monitored by changes in holding current) or input resistance were observed.

A previous

Discussion

We have shown that LFS, which mimics pathological cortically driven bursting activity in STN, promoted potentiation of glutamatergic (cortico-subthalamic) synaptic inputs but only in dopamine-intact tissue. Similarly, HFS promotes synaptic depression but only in dopamine-depleted tissue, indicating that the beneficial effects of DBS may be mediated, in part, by depression of cortico-subthalamic synapses (Fig. 5). Taken together, these results suggest that the synaptic weight of the

Acknowledgments

This work is supported by Parkinson's UK grant G-071 and The Medical Research Council, UK.

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In brief, the whole brain was rapidly removed from the animal under isoflurane anesthesia, and placed into ice-cold oxygenated (95% O2/5% CO2) choline-based cutting solution (containing [in mM] 87 NaCl, 37.5 choline chloride, 25 NaHCO3, 25 glucose, 2.5 KCl, 1.25 NaH2PO4, 7 MgCl2, and 0.5 CaCl2). Parasagittal brain slices (270 and 370 μm in thickness for mice and rats, respectively) that preserve most BG networks, particularly the STN and the cortico-subthalamic pathway (Bosch et al., 2012; Huang et al., 2017; Chu et al., 2017; Froux et al., 2018; Yamawaki et al., 2012), were cut on a vibratome (Leica VT1200S, Germany). According to the brain atlas and literatures (e.g., refer to Hamani et al., 2004, 2017; Beurrier et al., 2006; Oh et al., 2014), our preparation of STN slices should preserve only the cortico-subthalamic fibers but not the thalamo-subthalamic parafascicular fibers.
Parkinson’s disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K⁺ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.
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When stable measurements were obtained, baseline (5–10 min), treatment/vehicle (10–15 min), and APV at 400 μM (5 min) were sequentially recorded with a delivered puff of NMDA plus glycine at 30–60 s intervals. EPSCs were stimulated by 50–500 μA current injection for 0.1 ms using a bipolar tungsten stimulating electrode (MX211EW(PC3), FHC, Bowdoin, ME) positioned near the internal capsule fibers rostral to the STN (Baufreton et al., 2009; Yamawaki et al., 2012) or positioned at Schaffer collateral for hippocampal recordings. EPSCs were stimulated every 30–60 s, and recorded at a holding potential of −40mV for STN neurons and +40 mV for hippocampal neurons.
NMDA receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. The diverse functions of these receptors are tuned by deploying different combinations of GluN1 and GluN2 subunits (GluN2A-D) to form either diheteromeric NMDA receptors, which contain two GluN1 and two identical GluN2 subunits, or triheteromeric NMDA receptors, which contain two GluN1 and two distinct GluN2 subunits. Here, we characterize PTC-174, a novel positive allosteric modulator (PAM) of receptors containing GluN2C or GluN2D subunits. PTC-174 potentiates maximal current amplitudes by 1.8-fold for diheteromeric GluN1/2B receptors and by > 10-fold for GluN1/2C and GluN1/2D receptors. PTC-174 also potentiates responses from triheteromeric GluN1/2B/2D and GluN1/2A/2C receptors by 4.5-fold and 1.7-fold, respectively. By contrast, PTC-174 produces partial inhibition of responses from diheteromeric GluN1/2A and triheteromeric GluN1/2A/2B receptors. PTC-174 increases potencies of co-agonists glutamate and glycine by 2- to 5-fold at GluN1/2C and GluN1/2D receptors, and NMDA receptor activation facilitates allosteric modulation by PTC-174. At native NMDA receptors in GluN2D-expressing subthalamic nucleus neurons, PTC-174 increases the amplitude of responses to NMDA application and slows the decay of excitatory postsynaptic currents (EPSCs) evoked by internal capsule stimulation. Furthermore, PTC-174 increases the amplitude and slows the decay of EPSCs in hippocampal interneurons, but has not effect on the amplitudes of NMDA receptor-mediated EPSCs in hippocampal CA1 pyramidal neurons. Thus, PTC-174 provides a useful new pharmacological tool to investigate the molecular pharmacology and physiology of GluN2C- and GluN2D-containing NMDA receptors.
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In this context, and to summarize: i) a direct monosynaptic cortico-STN excitatory post-synaptic evoked potential is recorded in physiological and pathological states (Yamawaki et al., 2012); This could support rapid communication between cortex and BG targets that bypasses the striatum without disrupting slower rate coding pathways (Farries et al., 2010); ii) STN-DBS may alter anti-dromically the axonal efficiency between motor cortex and BG (and may represent a neglected mechanism of action providing fast behavioural transitions) (Walker et al., 2011).
Deep brain stimulation (DBS) has become a standard therapy for Parkinson’s disease (PD) and it is also currently under investigation for other neurological and psychiatric disorders. Although many scientific, clinical and ethical issues are still unresolved, DBS delivered into the subthalamic nucleus (STN) has improved the quality of life of several thousands of patients.
The mechanisms underlying STN-DBS have been debated extensively in several reviews; less investigated are the biochemical consequences, which are still under scrutiny. Crucial and only partially understood, for instance, are the complex interplays occurring between STN-DBS and levodopa (LD)-centred therapy in the post-surgery follow-up.
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The present article will discuss the neurochemical changes promoted by STN-DBS and will document the main results obtained in microdialysis studies. Furthermore, we will also examine the preliminary achievements of voltammetry applied to humans, and discuss new hypothetical investigational routes, taking into account novel players such as glia, or subcortical regions such as the pedunculopontine (PPN) area.
Our further understanding of specific changes in brain chemistry promoted by STN-DBS would further disseminate its utilisation, at any stage of disease, avoiding an irreversible lesioning approach.
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In another scenario, stimulation frequency and differences in BG tissue components including grey matter differences in PD (Reetz et al., 2009) may change the effect of stimulation. In a study by Yamawaki et al., LFS was found to potentiate cortico-subthalamic synaptic inputs in dopamine intact tissues, while HFS promoted synaptic depression in dopamine depleted tissue (Yamawaki et al., 2012). Correspondingly, they suggested that, similar to our results, the modulation of these pathways by STN DBS relies on the dopaminergic state in the tissue, and the frequency of stimulation used (Yamawaki et al., 2012).
Chronic pain is one of the most common non-motor symptoms of Parkinson's disease (PD) affecting up to 85% of patients. Previous studies have established that reduced mechanical and thermal thresholds occur in both idiopathic PD patients and animal models of PD, suggesting that changes may occur in sensory processing circuits. Improvements in sensory thresholds are achieved using subthalamic nucleus (STN) deep brain stimulation (DBS), however the mechanism by which this occurs remains unresolved.
We examined unilateral medial forebrain bundle 6-hydroxydopamine (6OHDA) rat model of PD to determine whether STN DBS alters neuronal firing rates in brain areas involved in ascending and descending pain processing. Specifically, single unit in vivo recordings were conducted in the anterior cingulate cortex (ACC), the periaqueductal grey (PAG), and the ventral posteriolateral nucleus of the thalamus (VPL), before, during and after stimulation was applied to the STN at 50 or 150 Hz.
Sham and 6OHDA lesioned animals have similar neuronal firing activity in the VPL, ACC and PAG before stimulation was applied (p > 0.05). In 6OHDA lesioned rats, both low frequency stimulation (LFS) (p < 0.01) and high frequency stimulation (HFS) (p < 0.05) attenuated firing frequency in the ACC. In shams, only LFS decreased firing frequency. A subset of neurons in the PAG was significantly attenuated in both sham and 6OHDA lesioned animals during HFS and LFS (p < 0.05), while another subset of PAG neuronal activity significantly increased in 6OHDA lesioned rats during HFS (p < 0.05). Finally, low or high frequency STN DBS did not alter neuronal firing frequencies in the VPL.
Our results suggest that STN DBS alters neuronal firing in descending pain circuits. We hypothesize that STN DBS attenuates excitatory projections from the ACC to the PAG in 6OHDA lesioned rats. Following this, neurons in the PAG respond by either increasing (during HFS only) or decreasing (during both LFS and HFS), which may modulate descending facilitation or inhibition at the level of the spinal cord. Future work should address specific neuronal changes in the ACC and PAG that occur in a freely moving parkinsonian animal during a pain stimulus treated with STN DBS.

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¹: Present address: Department of Physiology, The Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.

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Cellular and Molecular NeuroscienceResearch PaperFrequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

Abstract

Highlights

Section snippets

Experimental procedures

Results

Discussion

Acknowledgments

Prog Neurobiol

Neuron

Exp Neurol

Brain Res

Trends Neurosci

Brain Res

Neuron

Exp Neurol

Clin Neurophysiol

Neuropharmacology

Neuroscience

Brain Res

Exp Neurol

J Neurol Sci

Prog Neurobiol

The subthalamic nucleus becomes a generator of bursts in the dopamine-depleted stateIts high frequency stimulation dramatically weakens transmission to the globus pallidus

Front Syst Neurosci

Presynaptic mechanism for long-term potentiation in the hippocampus

Nature

Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys

Eur J Neurosci

Mechanism of action of deep brain stimulation

Neurology

The primate subthalamic nucleusII. Neuronal activity in the MPTP model of parkinsonism

J Neurophysiol

The glutamate-enriched cortical and thalamic input to neurons in the subthalamic nucleus of the rat: convergence with GABA-positive terminals

J Comp Neurol

Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat

J Neurosci

Regulation of the timing and pattern of action potential generation in rat subthalamic neurones in vitro by GABA-A IPSPs

J Neurophysiol

Subthalamic nucleus neurones switch from single-spike activity to burst-firing mode

J Neurosci

Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease

J Neurosci

Long-term synaptic depression in the striatum: physiological and pharmacological characterization

J Neurosci

Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors

J Neurosci

Synaptic release of dopamine in the subthalamic nucleus

Eur J Neurosci

Deep brain stimulation mechanisms: beyond the concept of local functional inhibition

Eur J Neurosci

Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients

J Neurol Neurosurg Psychiatry

Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism

Brain Res

Reciprocal interactions between oscillatory activities of different frequencies in the subthalamic region of patients with Parkinson's disease

Eur J Neurosci

Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease

Mov Disord

Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans

Eur J Neurosci

Optical deconstruction of parkinsonian neural circuitry

Science

Cellular and Molecular Neuroscience
Research Paper
Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus