title: Differential Adulthood Onset mGlu5 Signaling Saves Prefrontal Function in the Fragile X Mouse.
abstract: The final maturation of the prefrontal cortex (PFC) continues into early adulthood and is delayed compared with other forebrain structures. However, how these late onset changes in the PFC relate to neurodevelopment disorders is poorly understood. Fragile X syndrome (FXS) is a prevalent neurogenetic disorder linked to deficits in PFC function. mGlu5 is an important molecular hub in the etiology of FXS. Thus we have examined changes in mGlu5 function in the PFC in a mouse model of FXS (Fmr1 knockout) during early adulthood and subsequent maturity. An unusual endophenotype was identified; during early adulthood (2-month-old) Fmr1 knockout mice show a severe deficit in mGlu5 dependent eCB synaptic plasticity; however, in 1-year-old this deficit self rectifies. This adulthood onset correction in mGlu5 function is linked to an engagement of TRPV1 receptors in 1-year-old mice. In 2-month-old Fmr1 knockout mice, mGlu5 mediated synaptic plasticity could be recovered with eCB system targeted drugs, but also by direct enhancement of mGlu5 function with a positive allosteric modulator. These results point to further refinements to the role of mGlu5 in FXS. Furthermore our findings suggest when studying neurodevelopmental disorders with a significant PFC phenotype consideration of late onset changes may be important.
authors: INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille 13009, France.
authors: Henry G S
authors: HGS
authors: Martin
authors: INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille 13009, France.
authors: Olivier
authors: O
authors: Lassalle
authors: INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille 13009, France.
authors: Olivier J
authors: OJ
authors: Manzoni
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D063388:Endocannabinoids / Q000378:metabolism; D058068:Endophenotypes; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000254:growth & development* / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D063388:Endocannabinoids; D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse
keywords: LTD; endocannabinoid; fragile X; mGlu5 receptor; synaptic plasticity