PMID- 37029391
OWN - NLM
STAT- MEDLINE
DCOM- 20230411
LR  - 20230810
IS  - 2040-2392 (Electronic)
VI  - 14
IP  - 1
DP  - 2023 Apr 7
TI  - The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, 
      motor learning and social behavior in a mouse model of Fragile X Syndrome.
PG  - 14
LID - 10.1186/s13229-023-00547-4 [doi]
LID - 14
AB  - 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 beta 
      adrenergic receptors. A reduction in extracellular Ca(2+) concentration restored 
      the readily releasable pool (RRP) size, basal synaptic transmission, beta 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.
CI  - (c) 2023. The Author(s).
FAU - Martin, Ricardo
AU  - Martin R
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, 
      Universidad Complutense, Instituto Universitario de Investigacion en 
      Neuroquimica, 28040, Madrid, Spain. rmartinh@ucm.es.
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain. rmartinh@ucm.es.
AD  - Departamento de Fisiologia, Facultad de Medicina, Universidad Complutense, 28040, 
      Madrid, Spain. rmartinh@ucm.es.
FAU - Suarez-Pinilla, Alberto Samuel
AU  - Suarez-Pinilla AS
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, 
      Universidad Complutense, Instituto Universitario de Investigacion en 
      Neuroquimica, 28040, Madrid, Spain.
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain.
FAU - Garcia-Font, Nuria
AU  - Garcia-Font N
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, 
      Universidad Complutense, Instituto Universitario de Investigacion en 
      Neuroquimica, 28040, Madrid, Spain.
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain.
AD  - Centre for Discovery Brain Sciences and Simon Initiative for Developing Brain, 
      University of Edinburgh, Edinburgh, EH89JZ, UK.
FAU - Laguna-Luque, M Luisa
AU  - Laguna-Luque ML
AD  - Division de Neurociencias, Universidad Pablo de Olavide, 41013, Sevilla, Spain.
FAU - Lopez-Ramos, Juan C
AU  - Lopez-Ramos JC
AD  - Division de Neurociencias, Universidad Pablo de Olavide, 41013, Sevilla, Spain.
FAU - Oset-Gasque, Maria Jesus
AU  - Oset-Gasque MJ
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain.
AD  - Departamento de Bioquimica, Facultad de Farmacia, Universidad Complutense, 
      Instituto Universitario Investigacion en Neuroquimica, 28040, Madrid, Spain.
FAU - Gruart, Agnes
AU  - Gruart A
AD  - Division de Neurociencias, Universidad Pablo de Olavide, 41013, Sevilla, Spain.
FAU - Delgado-Garcia, Jose M
AU  - Delgado-Garcia JM
AD  - Division de Neurociencias, Universidad Pablo de Olavide, 41013, Sevilla, Spain.
FAU - Torres, Magdalena
AU  - Torres M
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, 
      Universidad Complutense, Instituto Universitario de Investigacion en 
      Neuroquimica, 28040, Madrid, Spain.
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain.
FAU - Sanchez-Prieto, Jose
AU  - Sanchez-Prieto J
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Veterinaria, 
      Universidad Complutense, Instituto Universitario de Investigacion en 
      Neuroquimica, 28040, Madrid, Spain. jsprieto@ucm.es.
AD  - Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, 28040, 
      Madrid, Spain. jsprieto@ucm.es.
LA  - eng
GR  - BFU 2017-83292-R/Ministerio de Economia y Competitividad/
GR  - RD 16/0019/0009/Instituto de Salud Carlos III/
GR  - B2017/BMD-3688/Comunidad de Madrid/
GR  - PRE2018-083202/Ministerio de Ciencia e Innovacion/
GR  - PY18-82/Junta de Andalucia/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230407
PL  - England
TA  - Mol Autism
JT  - Molecular autism
JID - 101534222
RN  - 0 (VU 0155041)
RN  - YZN9W7P1BX (metabotropic glutamate receptor 4)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
SB  - IM
MH  - Male
MH  - Mice
MH  - Animals
MH  - *Long-Term Potentiation/physiology
MH  - *Fragile X Syndrome/metabolism
MH  - Fragile X Mental Retardation Protein/genetics/metabolism
MH  - Synaptic Transmission
MH  - Disease Models, Animal
MH  - Social Behavior
MH  - Mice, Knockout
PMC - PMC10082511
OTO - NOTNLM
OT  - Classical conditioning
OT  - Fmr1 KO
OT  - Parallel fiber-Purkinje cell synapse
OT  - RRP size
OT  - Vestibuloocular reflex
OT  - beta adrenergic receptor
COIS- The authors declare no competing interests.
EDAT- 2023/04/08 06:00
MHDA- 2023/04/11 06:42
PMCR- 2023/04/07
CRDT- 2023/04/07 23:35
PHST- 2022/09/12 00:00 [received]
PHST- 2023/04/03 00:00 [accepted]
PHST- 2023/04/11 06:42 [medline]
PHST- 2023/04/07 23:35 [entrez]
PHST- 2023/04/08 06:00 [pubmed]
PHST- 2023/04/07 00:00 [pmc-release]
AID - 10.1186/s13229-023-00547-4 [pii]
AID - 547 [pii]
AID - 10.1186/s13229-023-00547-4 [doi]
PST - epublish
SO  - Mol Autism. 2023 Apr 7;14(1):14. doi: 10.1186/s13229-023-00547-4.