TY - JOUR T1 - The activation of mGluR4 rescues parallel fiber LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome JF - bioRxiv DO - 10.1101/2022.04.29.490046 SP - 2022.04.29.490046 AU - Ricardo Martín AU - Alberto Samuel Suárez-Pinilla AU - Nuria García-Font AU - M. Luisa Laguna-Luque AU - Juan C. López-Ramos AU - María Jesús Oset-Gasque AU - Agnes Gruart AU - José M. Delgado-García AU - Magdalena Torres AU - José Sánchez-Prieto Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/30/2022.04.29.490046.abstract N2 - 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. ER -