title: Dysregulated NMDA-Receptor Signaling Inhibits Long-Term Depression in a Mouse Model of Fragile X Syndrome.
abstract: Fragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30-60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease.
  
  
  
  There is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, the Fmr1 knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype.
authors.affiliation: Institute of Biomedicine, Physiology, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Anna Karina Hugger
authors.identifier: 0000-0003-1645-1626
authors.initials: AK
authors.lastname: Toft
authors.affiliation: Institute of Biomedicine, Physiology, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Camilla Johanne
authors.initials: CJ
authors.lastname: Lundbye
authors.affiliation: Institute of Biomedicine, Physiology, Aarhus University, 8000 Aarhus, Denmark tbanke@biomed.au.dk.
authors.forename: Tue G
authors.identifier: 0000-0001-8417-4400
authors.initials: TG
authors.lastname: Banke
mesh_terms: D000367:Age Factors; D000818:Animals; D001703:Biophysics; D056654:CA3 Region, Hippocampal / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018683:Excitatory Amino Acid Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D016194:Receptors, N-Methyl-D-Aspartate; C497684:Fmr1 protein, mouse; C010117:3,4-dihydroxyphenylglycol
keywords: GluN2B; NMDA receptor antagonists; autism; fragile X; long-term depression; mGluR