Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome.
The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1KO mice from 2 to 12 months. In young adult Fmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1KO mice, which may correlate to some of the complex age-related deficits in FXS.
INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille, France.
Henry G S
HGS
Martin
INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille, France.
Olivier
O
Lassalle
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
Jonathan T
JT
Brown
INSERM U901, Marseille 13009, France.|INMED, Marseille 13009, France.|Université de Aix-Marseille, UMR S901, Marseille, France.
Olivier J
OJ
Manzoni
D000200:Action Potentials; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D051860:Fragile X Messenger Ribonucleoprotein 1; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C121465:6-methyl-2-(phenylethynyl)pyridine
Fragile X; LTP; NMDA receptor; mGlu receptor; synaptic plasticity