The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome

Background Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic protein...

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Autores: Martín Herranz, Ricardo, Suárez Pinilla, Alberto Samuel, García Font, Nuria, Laguna Luque, María Luisa, López-Ramos, Juan Carlos, Oset Gasque, María Jesús, Gruart, Agnes, Delgado-García, José María, Torres Molina, Magdalena Isabel, Sánchez-Prieto Borja, José
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/131442
Acceso en línea:https://hdl.handle.net/20.500.14352/131442
Access Level:acceso abierto
Palabra clave:612
Parallel fiber-Purkinje cell synapse
β adrenergic receptor
RRP size
Fmr1 KO
Classical conditioning
Vestibuloocular reflex
Ciencias Biomédicas
2490 Neurociencias
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spelling The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X SyndromeMartín Herranz, RicardoSuárez Pinilla, Alberto SamuelGarcía Font, NuriaLaguna Luque, María LuisaLópez-Ramos, Juan CarlosOset Gasque, María JesúsGruart, AgnesDelgado-García, José MaríaTorres Molina, Magdalena IsabelSánchez-Prieto Borja, José612Parallel fiber-Purkinje cell synapseβ adrenergic receptorRRP sizeFmr1 KOClassical conditioningVestibuloocular reflexCiencias Biomédicas2490 NeurocienciasBackground Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment. Methods We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4. Results We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca2+ concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice. Limitations We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells. Conclusions Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.Springer NatureUniversidad Complutense de Madrid20232023-04-0720232023-04-07journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/131442reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1314422026-06-02T12:44:21Z
dc.title.none.fl_str_mv The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
title The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
spellingShingle The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
Martín Herranz, Ricardo
612
Parallel fiber-Purkinje cell synapse
β adrenergic receptor
RRP size
Fmr1 KO
Classical conditioning
Vestibuloocular reflex
Ciencias Biomédicas
2490 Neurociencias
title_short The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
title_full The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
title_fullStr The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
title_full_unstemmed The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
title_sort The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
dc.creator.none.fl_str_mv Martín Herranz, Ricardo
Suárez Pinilla, Alberto Samuel
García Font, Nuria
Laguna Luque, María Luisa
López-Ramos, Juan Carlos
Oset Gasque, María Jesús
Gruart, Agnes
Delgado-García, José María
Torres Molina, Magdalena Isabel
Sánchez-Prieto Borja, José
author Martín Herranz, Ricardo
author_facet Martín Herranz, Ricardo
Suárez Pinilla, Alberto Samuel
García Font, Nuria
Laguna Luque, María Luisa
López-Ramos, Juan Carlos
Oset Gasque, María Jesús
Gruart, Agnes
Delgado-García, José María
Torres Molina, Magdalena Isabel
Sánchez-Prieto Borja, José
author_role author
author2 Suárez Pinilla, Alberto Samuel
García Font, Nuria
Laguna Luque, María Luisa
López-Ramos, Juan Carlos
Oset Gasque, María Jesús
Gruart, Agnes
Delgado-García, José María
Torres Molina, Magdalena Isabel
Sánchez-Prieto Borja, José
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 612
Parallel fiber-Purkinje cell synapse
β adrenergic receptor
RRP size
Fmr1 KO
Classical conditioning
Vestibuloocular reflex
Ciencias Biomédicas
2490 Neurociencias
topic 612
Parallel fiber-Purkinje cell synapse
β adrenergic receptor
RRP size
Fmr1 KO
Classical conditioning
Vestibuloocular reflex
Ciencias Biomédicas
2490 Neurociencias
description Background Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment. Methods We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4. Results We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca2+ concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice. Limitations We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells. Conclusions Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-04-07
2023
2023-04-07
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/131442
url https://hdl.handle.net/20.500.14352/131442
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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