RT Journal Article
SR Electronic
T1 The activation of mGluR4 rescues parallel fiber LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.29.490046
DO 10.1101/2022.04.29.490046
A1 Ricardo Martín
A1 Alberto Samuel Suárez-Pinilla
A1 Nuria García-Font
A1 M. Luisa Laguna-Luque
A1 Juan C. López-Ramos
A1 María Jesús Oset-Gasque
A1 Agnes Gruart
A1 José M. Delgado-García
A1 Magdalena Torres
A1 José Sánchez-Prieto
YR 2022
UL http://biorxiv.org/content/early/2022/04/30/2022.04.29.490046.abstract
AB Fragile X patients and mice lacking the Fragile X Mental Retardation Protein (FMRP) suffer from multiple behavioral alterations, including deficits in motor learning. We found that enhanced synaptic vesicle (SV) docking in cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only occludes further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP). A reduction in extracellular Ca2+ restored the readily releasable pool (RRP) size, rescuing β adrenergic receptor-mediated potentiation and parallel fiber LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and parallel fiber LTP. Moreover, when injected into Fmr1KO mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as improving the social behavior of these mice. Thus, pharmacological activation of mGluRs may offer therapeutic relief for motor learning and social deficits in Fragile X Syndrome.Competing Interest StatementThe authors have declared no competing interest.