Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex.

The two principal movement-suppressing pathways of the basal ganglia, the so-called hyperdirect and indirect pathways, interact within the subthalamic nucleus (STN). An appropriate level and pattern of hyperdirect pathway cortical excitation and indirect pathway external globus pallidus (GPe) inhibition of the STN are critical for normal movement and are greatly perturbed in Parkinson's disease. Here we demonstrate that motor cortical inputs to the STN heterosynaptically regulate, through activation of postsynaptic NMDA receptors, the number of functional GABAA receptor-mediated GPe-STN inputs. Therefore, a homeostatic mechanism, intrinsic to the STN, balances cortical excitation by adjusting the strength of GPe inhibition. However, following the loss of dopamine, excessive cortical activation of STN NMDA receptors triggers GPe-STN inputs to strengthen abnormally, contributing to the emergence of pathological, correlated activity.

• Publication year

  2015

• Venue

  Neuron

• Publication date

  2015-01-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.neuron.2014.12.022PMID 25578364PMCID PMC4304914
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neurobiology of Disease Subthalamic Nucleus Neurons Are Synchronized to Primary Motor Cortex Local Field Potentials in Parkinson ’ s Disease

  2013influential reference
• The Subthalamic Nucleus Is One of Multiple Innervation Sites for Long-Range Corticofugal Axons: A Single-Axon Tracing Study in the Rat

  2012cited by this paper
• Dichotomous Organization of the External Globus Pallidus

  2012influential reference
• Heterosynaptic long‐term potentiation at interneuron–principal neuron synapses in the amygdala requires nitric oxide signalling

  2012influential reference
• Proliferation of External Globus Pallidus-Subthalamic Nucleus Synapses following Degeneration of Midbrain Dopamine Neurons

  2012cited by this paper
• Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine.

  2011cited by this paper
• Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement.

  2011cited by this paper
• Modulation of striatal projection systems by dopamine.

  2011cited by this paper
• Subthalamo‐pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia

  2011cited by this paper
• Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism

  2011cited by this paper
• GABAA receptor trafficking-mediated plasticity of inhibitory synapses.

  2011cited by this paper
• Long-term plasticity at inhibitory synapses.

  2011influential reference
• The dynamic modulation of GABA(A) receptor trafficking and its role in regulating the plasticity of inhibitory synapses.

  2011cited by this paper
• New insights into the relationship between dopamine, beta oscillations and motor function.

  2011influential reference
• The organization of the forelimb representation of the C57BL/6 mouse motor cortex as defined by intracortical microstimulation and cytoarchitecture.

  2011cited by this paper
• Conditions for the Generation of Beta Oscillations in the Subthalamic Nucleus–Globus Pallidus Network

  2010cited by this paper
• HCN Channelopathy in External Globus Pallidus Neurons in Models of Parkinson’s Disease

  2010cited by this paper
• Postsynaptic Spiking Homeostatically Induces Cell-Autonomous Regulation of Inhibitory Inputs via Retrograde Signaling

  2010cited by this paper
• Selective Participation of Somatodendritic HCN Channels in Inhibitory But Not Excitatory Synaptic Integration in Neurons of the Subthalamic Nucleus

  2010cited by this paper
• Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

  2010influential reference
• The cell biology of synaptic inhibition in health and disease.

  2010cited by this paper
• GABAA receptors, gephyrin and homeostatic synaptic plasticity

  2010cited by this paper
• Microcircuitry coordination of cortical motor information in self-initiation of voluntary movements

  2009cited by this paper
• Sparse but selective and potent synaptic transmission from the globus pallidus to the subthalamic nucleus.

  2009cited by this paper
• Short-Latency Visual Input to the Subthalamic Nucleus Is Provided by the Midbrain Superior Colliculus

  2009cited by this paper
• Disrupted Dopamine Transmission and the Emergence of Exaggerated Beta Oscillations in Subthalamic Nucleus and Cerebral Cortex

  2008influential reference
• Pathophysiology of parkinsonism.

  2008influential reference
• Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity

  2008influential reference
• Species differences in the localization of soluble guanylyl cyclase subunits in monkey and rat brain

  2007influential reference
• Pathological synchronization in Parkinson's disease: networks, models and treatments.

  2007influential reference
• Opioids block long-term potentiation of inhibitory synapses

  2007influential reference
• Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys

  2007influential reference
• NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABAA Receptors

  2007influential reference
• Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models

  2006cited by this paper
• Cortical Inputs and GABA Interneurons Imbalance Projection Neurons in the Striatum of Parkinsonian Rats

  2006influential reference
• Activity-Dependent Bidirectional Modification of Inhibitory Synaptic Transmission in Rat Subthalamic Neurons

  2006cited by this paper
• Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABAA and GABAB Receptors

  2005cited by this paper
• Enhancement of Excitatory Synaptic Integration by GABAergic Inhibition in the Subthalamic Nucleus

  2005cited by this paper
• Dopamine depletion alters responses to glutamate and GABA in the rat subthalamic nucleus

  2005cited by this paper
• Rhythmic Bursting in the Cortico-Subthalamo-Pallidal Network during Spontaneous Genetically Determined Spike and Wave Discharges

  2005cited by this paper
• GABAB Receptor‐ and Metabotropic Glutamate Receptor‐Dependent Cooperative Long‐Term Potentiation of Rat Hippocampal GABAA Synaptic Transmission

  2003cited by this paper
• Synaptic plasticity in rat subthalamic nucleus induced by high‐frequency stimulation

  2003cited by this paper
• Apamin-Sensitive Small Conductance Calcium-Activated Potassium Channels, through their Selective Coupling to Voltage-Gated Calcium Channels, Are Critical Determinants of the Precision, Pace, and Pattern of Action Potential Generation in Rat Subthalamic Nucleus Neurons In Vitro

  2003cited by this paper
• Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs.

  2002cited by this paper
• Enhanced Synchrony among Primary Motor Cortex Neurons in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Primate Model of Parkinson's Disease

  2002cited by this paper
• Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway.

  2002cited by this paper
• Activity Patterns in a Model for the Subthalamopallidal Network of the Basal Ganglia

  2002cited by this paper
• Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network.

  2001cited by this paper
• Excitatory postsynaptic potentials trigger a plateau potential in rat subthalamic neurons at hyperpolarized states.

  2001cited by this paper
• Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons.

  2001cited by this paper
• Role of the basal ganglia in the control of purposive saccadic eye movements.

  2000cited by this paper
• Unveiling synaptic plasticity: a new graphical and analytical approach.

  2000cited by this paper
• Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei.

  2000influential reference
• Relationships between the Prefrontal Cortex and the Basal Ganglia in the Rat: Physiology of the Cortico-Nigral Circuits

  1999influential reference
• Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias.

  1999cited by this paper
• Long-term potentiation--a decade of progress?

  1999influential reference
• Relationships between the Prefrontal Cortex and the Basal Ganglia in the Rat: Physiology of the Corticosubthalamic Circuits

  1998cited by this paper
• Microcircuitry of the direct and indirect pathways of the basal ganglia.

  1998cited by this paper
• Subregion- and cell type-restricted gene knockout in mouse brain.

  1996cited by this paper
• In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit

  1995cited by this paper
• Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat

  1995cited by this paper
• Nitric oxide synthase mRNA expression in human subthalamic nucleus, striatum and globus pallidus: implications for basal ganglia function.

  1994influential reference
• Glutamate Receptors in the Central Nervous System

  1993cited by this paper
• Response characteristics of subthalamic neurons to the stimulation of the sensorimotor cortex in the rat.

  1993cited by this paper
• Basal ganglia intrinsic circuits and their role in behavior.

  1993cited by this paper
• Disinhibition as a basic process in the expression of striatal functions.

  1990cited by this paper
• Topographical and Synaptic Organization of the GABA‐Containing Pallidosubthalamic Projection in the Rat

  1990cited by this paper
• The functional anatomy of basal ganglia disorders.

  1989influential reference
• Topographical projections of the cerebral cortex to the subthalamic nucleus

  1985cited by this paper
• Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey

  1978cited by this paper

• Dysfunction of subthalamic dopaminergic circuitry contributes to anxiety- and depression-like behaviors in 6-OHDA lesion-induced hemiparkinsonian mice

  2025cites this paper
• Histamine Modulation of the Basal Ganglia Circuitry in the Motor Symptoms of Parkinson's Disease

  2025cites this paper
• Calcium-based synaptic and structural plasticity link pathological activity to synaptic reorganization in Parkinson’s disease

  2025influential citation
• Harnessing neuronal plasticity for sustained symptom relief with DBS.

  2025cites this paper
• What Are Current Concepts on the Functional Organization of the Globus Pallidus Externus and Its Potential Role in Parkinson Disease?

  2025cites this paper
• Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex

  2024cites this paper
• The promotion‐like effect of the M1‐STN hyperdirect pathway induced by ccPAS enhanced balance performances: From the perspective of brain connectivity

  2024cites this paper
• Pathophysiology of Motor Control Abnormalities in Parkinson's Disease.

  2024cites this paper
• Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges

  2024cites this paper
• Non-conventional deep brain stimulation in a network model of movement disorders

  2024cites this paper
• Motor cortex directly excites the output nucleus of the basal ganglia, the substantia nigra pars reticulata

  2024cites this paper
• Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation

  2024cites this paper
• Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles

  2024cites this paper
• Unraveling the Complexity of Parkinson's Disease: Insights into Pathogenesis and Precision Interventions

  2024cites this paper
• Circuit-Specific Deep Brain Stimulation Provides Insights into Movement Control.

  2024cites this paper
• Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation

  2024cites this paper
• Rhythmic modulation of subthalamo-pallidal interactions depends on synaptic rewiring through inhibitory plasticity

  2024influential citation
• Impact of Network Topology on Neural Synchrony in a Model of the Subthalamic Nucleus-Globus Pallidus Circuit

  2023cites this paper
• A role for the subthalamic nucleus in aversive learning.

  2023cites this paper
• Synaptic network structure shapes cortically evoked spatio-temporal responses of STN and GPe neurons in a computational model

  2023cites this paper
• The transcription regulator Lmo3 is required for the development of medial ganglionic eminence derived neurons in the external globus pallidus.

  2023cites this paper
• The dendritic engram

  2023cites this paper
• Cell and circuit complexity of the external globus pallidus

  2023cites this paper
• Exploration behavior after reversals is predicted by STN-GPe synaptic plasticity in a basal ganglia model

  2023cites this paper
• Neural pathway connectivity and discharge changes between M1 and STN in Hemiparkinsonian Rats.

  2023cites this paper
• Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice.

  2023cites this paper
• Subthalamic neurons interact with nigral dopaminergic neurons to regulate movement in mice

  2023cites this paper
• Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson's disease

  2023cites this paper
• White matter microstructure in Parkinson’s disease with and without elevated rapid eye movement sleep muscle tone

  2022cites this paper
• Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit

  2022cites this paper
• Spike-Timing-Dependent Plasticity Mediated by Dopamine and its Role in Parkinson’s Disease Pathophysiology

  2022influential citation
• Histamine bidirectionally regulates the intrinsic excitability of parvalbumin‐positive neurons in the lateral globus pallidus and promotes motor behaviour

  2022cites this paper
• Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity

  2022cites this paper
• Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice

  2022cites this paper
• The transcription regulator Lmo3 is required for cell fate specification in the external globus pallidus

  2022cites this paper
• Inhibitory Spike-Timing-Dependent Plasticity Can Account for Pathological Strengthening of Pallido-Subthalamic Synapses in Parkinson’s Disease

  2022influential citation
• Hypothetical Mechanism of Resting Tremor in Parkinson’s Disease

  2022cites this paper
• Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

  2021cites this paper
• Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

  2021cites this paper
• Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia

  2021cites this paper
• Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease

  2021cites this paper
• The external pallidum: think locally, act globally

  2021cites this paper
• Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus

  2021cites this paper
• Mild stress accumulation limits GABAergic synaptic plasticity in the lateral habenula

  2021cites this paper
• Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

  2021cites this paper
• Differential modulation of subthalamic projection neurons by short-term and long-term electrical stimulation in physiological and parkinsonian conditions

  2021cites this paper
• Heterosynaptic Plasticity and the Experience-Dependent Refinement of Developing Neuronal Circuits

  2021cites this paper
• Subthalamic Burst Firing: A Pathophysiological Target in Parkinson's disease.

  2021cites this paper
• Dopamine depletion can be predicted by the aperiodic component of subthalamic local field potentials

  2021cites this paper
• Therapeutic Deep Brain Stimulation Disrupts Subthalamic Nucleus Activity Dynamics in Parkinsonian Mice

  2021cites this paper
• Biophysical and Architectural Mechanisms of Subthalamic Theta under Response Conflict

  2021cites this paper
• White matter microstructure in Parkinson's disease with and without elevated REM sleep muscle tone

  2021cites this paper
• A neurocomputational model of the basal ganglia for the analysis of motor deficits after dopaminergic loss in Parkinson’s disease

  2021cites this paper
• Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats

  2021cites this paper
• Altered Dynamic Information Flow through the Cortico-Basal Ganglia Pathways Mediates Parkinson’s Disease Symptoms

  2021cites this paper
• Changes in Excitability Properties of Ventromedial Motor Thalamic Neurons in 6-OHDA Lesioned Mice

  2020influential citation
• Synaptic and cellular plasticity in Parkinson’s disease

  2020cites this paper
• Dysregulation of external globus pallidus‐subthalamic nucleus network dynamics in parkinsonian mice during cortical slow‐wave activity and activation

  2020influential citation
• Parvalbumin+ and Npas1+ Pallidal Neurons Have Distinct Circuit Topology and Function

  2020cites this paper
• The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism

  2020cites this paper
• Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease.

  2020cites this paper
• Morphological changes in the subthalamic nucleus of people with mild-to-moderate Parkinson’s disease: a 7T MRI study

  2020cites this paper
• The effect of STN DBS on modulating brain oscillations: consequences for motor and cognitive behavior

  2020cites this paper
• Cortical Control of Subthalamic Neuronal Activity through the Hyperdirect and Indirect Pathways in Monkeys

  2020cites this paper
• Pre-proof “ Stopping for knowledge ” : The sense of beauty in the perception-action cycle

  2020cites this paper
• Deep brain stimulation: a review of the open neural engineering challenges

  2020cites this paper
• Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonian Mice

  2020cites this paper
• My Neighbour Hetero-deconstructing the mechanisms underlying heterosynaptic plasticity.

  2020cites this paper
• Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

  2020cites this paper
• Autonomous oscillations and phase-locking in a biophysically detailed model of the STN-GPe network

  2019cites this paper
• Analysis of temporally evolved nanoparticle-protein corona highlighted the potential ability of gold nanoparticles to stably interact with proteins and influence the major biochemical pathways in Brassica juncea.

  2019cites this paper
• Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

  2019cites this paper
• State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice

  2019cites this paper
• Connectivity and Dynamics Underlying Synaptic Control of the Subthalamic Nucleus

  2019cites this paper
• Ionic Mechanisms Underlying the Excitatory Effect of Orexin on Rat Subthalamic Nucleus Neurons

  2019cites this paper
• Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in Parkinsonian mice

  2019cites this paper
• Cellular and Synaptic Dysfunctions in Parkinson’s Disease: Stepping Out of the Striatum

  2019influential citation
• Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons

  2019cites this paper
• The Use of Optogenetic and DREADDs Techniques: Applications to the Behavioral Pathology in Parkinson’s Disease (Review)

  2019cites this paper
• Changing views of the pathophysiology of Parkinsonism

  2019cites this paper
• Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update—I. Hypokinetic-rigid movement disorders

  2019cites this paper
• Étude par traçage neuronal unitaire de la voie corticosubthalamique hyperdirecte chez le singe

  2018cites this paper
• Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications

  2018cites this paper
• Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction

  2018cites this paper
• Significance and Translational Value of High-Frequency Cortico-Basal Ganglia Oscillations in Parkinson’s Disease

  2018cites this paper
• Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits

  2018cites this paper
• D5 dopamine receptors control glutamatergic AMPA transmission between the motor cortex and subthalamic nucleus

  2018cites this paper
• Brain plasticity and sleep: Implication for movement disorders

  2018cites this paper
• Changes in neuronal activity of cortico‐basal ganglia–thalamic networks induced by acute dopaminergic manipulations in rats

  2018cites this paper
• Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation.

  2018cites this paper
• NMDA receptor blockade ameliorates abnormalities of spike firing of subthalamic nucleus neurons in a parkinsonian nonhuman primate

  2018cites this paper
• Advances in optogenetic and chemogenetic methods to study brain circuits in non-human primates

  2018cites this paper
• Closing gaps in brain disease-from overlapping genetic architecture to common motifs of synapse dysfunction.

  2018cites this paper
• Harnessing Pallidal Cell-Type Diversity to Treat Neurological Disorders

  2017cites this paper
• Compensatory mechanisms in Parkinson's disease: Circuits adaptations and role in disease modification.

  2017cites this paper
• Chapter 49 – Deep-Brain Stimulation for Neurologic and Neuropsychiatric Disorders

  2017cites this paper
• Revealing a Role for NMDA Receptors in Regulating STN Inputs following the Loss of Dopamine.

  2017influential citation
• Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice

  2017cites this paper
• Anatomy, Physiology, and Clinical Syndromes of the Basal Ganglia: A Brief Review.

  2017cites this paper
• Sparse pallidal connections shape synchrony in a network model of the basal ganglia

  2017cites this paper