Proliferation of External Globus Pallidus-Subthalamic Nucleus Synapses following Degeneration of Midbrain Dopamine Neurons

The symptoms of Parkinson's disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD, the GPe and STN exhibit hypoactivity and hyperactivity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons, abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2–3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern, and synchronization of STN activity, electrophysiological, molecular, and anatomical measures of GPe–STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: (1) the frequency (but not the amplitude) of mIPSCs increased by ∼70%; (2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ∼60% and ∼70%, respectively; (3) mRNA encoding α1, β2, and γ2 GABAA receptor subunits increased by 15–30%; (4) the density of postsynaptic gephyrin and γ2 subunit coimmunoreactive structures increased by ∼40%, whereas the density of vesicular GABA transporter and bassoon coimmunoreactive axon terminals was unchanged; and (5) the number of ultrastructurally defined synapses per GPe–STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe–STN axon terminal, to substantial strengthening of the GPe–STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.

[1]  Steven Finkbeiner,et al.  Rapid Target-Specific Remodeling of Fast-Spiking Inhibitory Circuits after Loss of Dopamine , 2011, Neuron.

[2]  P. Brown,et al.  New insights into the relationship between dopamine, beta oscillations and motor function , 2011, Trends in Neurosciences.

[3]  Steven W. Johnson,et al.  Excitatory effects of dopamine on subthalamic nucleus neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa , 2002, Brain Research.

[4]  Theofilos G. Papadopoulos,et al.  The Role of Collybistin in Gephyrin Clustering at Inhibitory Synapses: Facts and Open Questions , 2011, Front. Cell. Neurosci..

[5]  R. Carroll,et al.  NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABAA Receptors , 2007, The Journal of Neuroscience.

[6]  Raymond J. Dolan,et al.  Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism , 2011, PLoS Comput. Biol..

[7]  Jozsef Csicsvari,et al.  Disrupted Dopamine Transmission and the Emergence of Exaggerated Beta Oscillations in Subthalamic Nucleus and Cerebral Cortex , 2008, The Journal of Neuroscience.

[8]  Steven W. Johnson,et al.  Dopamine depletion alters responses to glutamate and GABA in the rat subthalamic nucleus , 2005, Neuroreport.

[9]  S. Johnson,et al.  Presynaptic dopamine D2 and muscarine M3 receptors inhibit excitatory and inhibitory transmission to rat subthalamic neurones in vitro , 2000, The Journal of physiology.

[10]  John R. Terry,et al.  Conditions for the Generation of Beta Oscillations in the Subthalamic Nucleus–Globus Pallidus Network , 2010, The Journal of Neuroscience.

[11]  Y Agid,et al.  Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements , 2000, The European journal of neuroscience.

[12]  E. Jorgensen,et al.  Identification and characterization of the vesicular GABA transporter , 1997, Nature.

[13]  Y. Smith,et al.  Microcircuitry of the direct and indirect pathways of the basal ganglia. , 1998, Neuroscience.

[14]  C. Garner,et al.  Bassoon, a Novel Zinc-finger CAG/Glutamine-repeat Protein Selectively Localized at the Active Zone of Presynaptic Nerve Terminals , 1998, The Journal of cell biology.

[15]  D. Surmeier,et al.  Selective Participation of Somatodendritic HCN Channels in Inhibitory But Not Excitatory Synaptic Integration in Neurons of the Subthalamic Nucleus , 2010, The Journal of Neuroscience.

[16]  Charles J. Wilson,et al.  Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs. , 2002, Journal of neurophysiology.

[17]  Yumiko Yoshimura,et al.  State-Dependent Bidirectional Modification of Somatic Inhibition in Neocortical Pyramidal Cells , 2008, Neuron.

[18]  Paul Krack,et al.  Functional neurosurgery for movement disorders: a historical perspective. , 2009, Progress in brain research.

[19]  Z. Xiang,et al.  Activity-Dependent Bidirectional Modification of Inhibitory Synaptic Transmission in Rat Subthalamic Neurons , 2006, The Journal of Neuroscience.

[20]  D James Surmeier,et al.  Enhancement of Excitatory Synaptic Integration by GABAergic Inhibition in the Subthalamic Nucleus , 2005, The Journal of Neuroscience.

[21]  C. Gerfen,et al.  Modulation of striatal projection systems by dopamine. , 2011, Annual review of neuroscience.

[22]  P. Stanzione,et al.  The pharmacological blockade of medial forebrain bundle induces an acute pathological synchronization of the cortico–subthalamic nucleus–globus pallidus pathway , 2009, The Journal of physiology.

[23]  A. Sampson,et al.  Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models , 2006, Nature Neuroscience.

[24]  Jérôme Baufreton,et al.  D2‐like dopamine receptor‐mediated modulation of activity‐dependent plasticity at GABAergic synapses in the subthalamic nucleus , 2008, The Journal of physiology.

[25]  W Wisden,et al.  The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  Claus Lindbjerg Andersen,et al.  Normalization of Real-Time Quantitative Reverse Transcription-PCR Data: A Model-Based Variance Estimation Approach to Identify Genes Suited for Normalization, Applied to Bladder and Colon Cancer Data Sets , 2004, Cancer Research.

[27]  M. Bevan,et al.  Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABAA and GABAB Receptors , 2005, The Journal of Neuroscience.

[28]  S. Thein,et al.  Selection of housekeeping genes for gene expression studies in human reticulocytes using real-time PCR , 2006, BMC Molecular Biology.

[29]  A. Craig,et al.  Inhibitory Synapse Dynamics: Coordinated Presynaptic and Postsynaptic Mobility and the Major Contribution of Recycled Vesicles to New Synapse Formation , 2011, The Journal of Neuroscience.

[30]  M. Delong,et al.  Milestones in research on the pathophysiology of Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[31]  Pavel Osten,et al.  HCN Channelopathy in External Globus Pallidus Neurons in Models of Parkinson’s Disease , 2010, Nature Neuroscience.

[32]  Hitoshi Kita,et al.  Subthalamo‐pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia , 2011, The European journal of neuroscience.

[33]  Hagai Bergman,et al.  Akineto-rigid vs. tremor syndromes in Parkinsonism , 2009, Current opinion in neurology.

[34]  Jérôme Baufreton,et al.  Sparse but selective and potent synaptic transmission from the globus pallidus to the subthalamic nucleus. , 2009, Journal of neurophysiology.

[35]  Kristina D. Micheva,et al.  Single-Synapse Analysis of a Diverse Synapse Population: Proteomic Imaging Methods and Markers , 2010, Neuron.

[36]  Joshua L. Plotkin,et al.  Strain-Specific Regulation of Striatal Phenotype in Drd2-eGFP BAC Transgenic Mice , 2012, The Journal of Neuroscience.

[37]  I. Stanford,et al.  Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity , 2006, Neuroscience.

[38]  Peter Brown,et al.  Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity , 2008, The Journal of Neuroscience.

[39]  T. Schallert,et al.  CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury , 2000, Neuropharmacology.

[40]  T. Fuchs,et al.  GABAA Receptor Trafficking-Mediated Plasticity of Inhibitory Synapses , 2011, Neuron.

[41]  D. Chetkovich,et al.  HCN channels in behavior and neurological disease: Too hyper or not active enough? , 2011, Molecular and Cellular Neuroscience.

[42]  J. Kittler,et al.  The cell biology of synaptic inhibition in health and disease , 2010, Current Opinion in Neurobiology.

[43]  B. R. Sastry,et al.  Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei. , 2000, Journal of neurophysiology.

[44]  Peter Brown,et al.  Effects of dopamine depletion on information flow between the subthalamic nucleus and external globus pallidus. , 2011, Journal of neurophysiology.

[45]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[46]  M. Pfaffl,et al.  Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations , 2004, Biotechnology Letters.

[47]  J. Fritschy,et al.  GABAA receptors, gephyrin and homeostatic synaptic plasticity , 2010, The Journal of physiology.

[48]  Mark Farrant,et al.  Differences in Synaptic GABAA Receptor Number Underlie Variation in GABA Mini Amplitude , 1997, Neuron.

[49]  Tzong-Shiue Yu,et al.  Changes in the Gene Expression of GABAA Receptor α1 and α2 Subunits and Metabotropic Glutamate Receptor 5 in the Basal Ganglia of the Rats with Unilateral 6-Hydroxydopamine Lesion and Embryonic Mesencephalic Grafts , 2001, Experimental Neurology.

[50]  Mark J. West,et al.  Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias , 1999, Trends in Neurosciences.

[51]  M. Farrant,et al.  Setting the Time Course of Inhibitory Synaptic Currents by Mixing Multiple GABAA Receptor α Subunit Isoforms , 2012, The Journal of Neuroscience.