Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons
Identifieur interne : 000F92 ( Ncbi/Merge ); précédent : 000F91; suivant : 000F93Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons
Auteurs : Kai Y. Fan [États-Unis, Royaume-Uni] ; Jérôme Baufreton [États-Unis, France] ; D. James Surmeier [États-Unis] ; C. Savio Chan [États-Unis] ; Mark D. Bevan [États-Unis]Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 0270-6474 ] ; 2012.
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 hypo- and hyper-activity, 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 co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 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.
Url:
DOI: 10.1523/JNEUROSCI.5750-11.2012
PubMed: 23035084
PubMed Central: 3475197
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<front><div type="abstract" xml:lang="en"><p id="P2">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 hypo- and hyper-activity, 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<sub>A</sub>
receptor subunits increased by 15–30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 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.</p>
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Department of Biomedical Science, Western Bank, Sheffield, S10 2TN, UK</aff>
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Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293, 146 Rue Léo Saignât, 33076 Bordeaux Cedex, France</aff>
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corresponding author. To whom correspondence should be addressed. <email>m-bevan@northwestern.edu</email>
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<abstract><p id="P2">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 hypo- and hyper-activity, 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<sub>A</sub>
receptor subunits increased by 15–30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 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.</p>
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