title: Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons.
abstract: 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 GABA(A) 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.
authors.affiliation: Northwestern University, Physiology, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Fan
authors.forename: Jérôme
authors.initials: J
authors.lastname: Baufreton
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bevan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000473:pathology* / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005917:Globus Pallidus / Q000473:pathology* / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000473:pathology* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics; D020531:Subthalamic Nucleus / Q000473:pathology* / Q000503:physiopathology; D009435:Synaptic Transmission; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C498441:Bsn protein, mouse; D002352:Carrier Proteins; D007539:Isonicotinic Acids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C073441:gephyrin; D016627:Oxidopamine; D004298:Dopamine; C015300:isoguvacine