TY - JOUR
T1 - Optogenetic Activation of Striatopallidal Neurons Reveals Altered HCN Gating in DYT1 Dystonia
AU - Sciamanna, Giuseppe
AU - Ponterio, Giulia
AU - Vanni, Valentina
AU - Laricchiuta, Daniela
AU - Martella, Giuseppina
AU - Bonsi, Paola
AU - Meringolo, Maria
AU - Tassone, Annalisa
AU - Mercuri, Nicola Biagio
AU - Pisani, Antonio
N1 - Funding Information:
This work was supported by the Italian Ministry of Health “Ricerca Corrente” and Bachmann-Strauss “Prize for excellence in dystonia research 2019” (to A.P.), by project GR-2011-02350639 and Fondi 5 X MILLE (2017) (to G.S.), and by Dystonia Medical Research Foundation (DMRF), 2017 grant funding (to G.S.).
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/19
Y1 - 2020/5/19
N2 - Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dystonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancing in vivo HCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, identifying potential pharmacological targets for dystonia.
AB - Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dystonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancing in vivo HCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, identifying potential pharmacological targets for dystonia.
KW - basal ganglia, movement disorders, globus pallidus, dopamine receptor, channelopathy, synaptopathy, optogenetic
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U2 - 10.1016/j.celrep.2020.107644
DO - 10.1016/j.celrep.2020.107644
M3 - Article
C2 - 32433955
AN - SCOPUS:85084650964
VL - 31
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 7
M1 - 107644
ER -