NMDAR NR2A and NR2B specific PKC-dependent regulation of mGluR is defective in the Fragile X Syndrome mouse model

Research output: Contribution to conferencePosterResearch

  • Tue G. Banke
  • Anna Karina Toft, Denmark
  • Camilla Johanne Lundbye, Denmark
The Fragile X Syndrome (FXS) animal model, the Fmr1 knock-out (KO) mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD). However, surprisingly little information exists about other ion channels/receptors and their effects on FXS, including NMDA receptors (NMDAR). Here we focus on the two main types of hippocampal LTD: (1) NMDA-dependent, and (2) mGluR-dependent but NMDA-independent, at different developmental stages. We applied the mGluR agonist DHPG in the presence or absence of the NMDAR competitive antagonist, APV, hereby unmasking the NMDAR component in this process. As reported by several labs, using the field potential recording technique in acute slices from young mice (P30-40), application of DHPG, in the presence of APV, induced more LTD in the KO mouse than in the control mouse (41+/-5%, n=7 vs. 21+/-4%, n=5, P<0.05). In the absence of APV, DHPG induced the same amount of LTD in KO vs WT (39+/-6%, n=11 vs. 33+/-5%, n=7, P=0.2), suggesting that NMDARs play an insignificant role in DHPG-induced LTD in both the KO and WT mouse at this young developmental stage. As with young mice, in slices from mature WT mice (P60-80), there was no significant difference in DHPG-induced LTD in the absence of APV (28+/-6%, n=12) or in the presence of APV (32+/-5%, n=8). Equivalent LTD was obtained in the KO mouse in the presence of APV (36+/-6%, n=9). This was in sharp contrast to recordings from KO mice where we found in the absence of APV, no or very little LTD (7+/-5%, n=15). Similar results were observed when mature KO slices were preincubated with the protein kinase C activator (PMA), or inactivator (chelerythrine), suggesting that NMDAR activation leads to PKC regulation of mGluR-LTD. Surprisingly, preincubation WT with the NR2B specific NMDAR inhibitor CP-101.606 completely blocked DHPG-induced LTD. This blockage was reversed by either preincubation with PMA or by co-application of the NR2A antagonist TCN-201. In contrast, application of TCN-201 alone had no apparent effects. Our data suggest a model where NMDARs regulate mGluR-LTD through regulation of PKC. Furthermore, in this model it appears that NR2B activation stimulates PKC, while NR2A activation halts or reverses this effect. In addition, in the KO mice, the coupling between specific NMDAR subunits and mGluR-LTD activity through PKC seems defective in an age-dependent manner. These findings suggest strong developmental involvement of NMDARs in the pathophysiology of FXS and highlight a novel potential path for FXS treatment.
Original languageEnglish
Publication year2015
Publication statusPublished - 2015
EventNeuroscience 2015: Society for Neuroscience 2015 meeting - McCormick Place, Chicago, IL, United States
Duration: 17 Oct 201521 Oct 2015
Conference number: 45


ConferenceNeuroscience 2015
LocationMcCormick Place
CountryUnited States
CityChicago, IL

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