Bretin S , Louis C , Seguin L , Wagner S , Thomas JY , Challal S , Rogez N , Albinet K , Iop F , Villain N , Bertrand S , Krazem A , Bérachochéa D , Billiald S , Tordjman C , Cordi A , Bertrand D , Lestage P , Danober L .

             AMPA glutamate receptor complex
             regulation of neuronal synaptic plasticity

           MAJOR DEPRESSIVE DISORDER; MDD

	Fig 1. Chemical structure of S 47445.Chemical name of S 47455 is 8-cyclopropyl-3-[2-(3-fluorophenyl)ethyl]-7,8-dihydro-3H-[1,3]oxazino[6,5-g][1,2,3]benzotriazine-4,9-dione.
	Fig 2. Effects of S 47445 on native rat and human AMPA, NMDA or kainate receptors.(A) Typical currents evoked by AMPA, kainate or NMDA on oocytes injected with rat cortex or human hippocampal poly(A+) mRNA in absence or presence of 100 μM S 47445 recorded in the same cell. (B) Concentration-activity curves obtained with S 47445 on AMPA-, kainate- or NMDA-evoked current on oocytes injected with rat cortex poly(A+) mRNA (n = 3, 3 and 4, respectively). (C) Comparative effects of S 47445 on AMPA-evoked current on oocytes injected with either human hippocampal or rat cortex poly(A+) mRNA (n = 5 and 3, respectively). In (A), (B) and (C), cells were held at -60 mV. The amplitude of current evoked in the presence of S 47445 was normalized to unity versus the control current evoked by the agonist alone on the same oocytes (either 10 μM AMPA, 1 mM kainate or 300 μM NMDA/30 μM glycine). Results are expressed as mean ± SEM.
	Fig 3. GluA1, GluA2 and GluA4 subunits and splice variants selectivity of S 47445 at human AMPA receptors.(A) Typical examples of glutamate-evoked currents in absence and presence of 100 μM S 47445 obtained on the same oocyte expressing either GluA1 flip (GluA1i, n = 5) or flop (GluA1o, n = 3) variants. (B) Concentration response curves for S 47445 obtained in oocytes injected with GluA1i and GluA1o receptors. (C) Maximal fold potentiation (Emax) induced by S 47445 on homomeric GluA1 flip (GluA1i), GluA1 flop (GluA1o), GluA4 flip (GluA4i), GluA4 flop (GluA4o) and heteromeric GluA1/GluA2 or GluA4/GluA2 receptors. Emax is given as the amplitude of current evoked in the presence of S 47445 normalized to unity versus the control current evoked by glutamate alone on the same oocytes. n is indicated in brackets. ** p≤0.01 GluA1o versus GluA1i, unpaired T-test. # p≤0.05 GluA1 flop/ GluA2 flip (GluA1o/2i) versus GluA1 flip/ GluA2 flip (GluA1i/2i), Tukey’s test following significant one-way ANOVA performed on GluA1/GluA2 heterodimers. In (A), (B) and (C), cells were held at -80 mV. Values are mean ± SEM.
	Fig 4. Potentiation of the glutamate-evoked current in AMPA receptors expressed in HEK-293 cells.Typical current recorded in the whole cell configuration in response to a brief pulse of glutamate in control (gray line) and during exposure to S 47445 (black line). These data illustrate that exposure to a low concentration of S 47445 causes already a significant modification of the decay time of the response. Cell was held at -80 mV. Plot of the concentration activation curve recorded in control and in presence of 0.1 μM S 47445 illustrates that this compound causes a left shift of the curve and increase of the maximal amplitude (n = 4).
	Fig 5. Potentiation of the glutamate-evoked current in GluA1flop/GluA2flip AMPA receptors expressed in Xenopus oocytes.Normalised currents in response to repetitive pulses of 10 μM glutamate applied for 20 s, 1/min and during exposure to low concentrations of S 47445 (0.1 and 0.3 μM). Currents were normalized to the mean of the first 5 recordings in vehicle conditions illustrated by the symbol (-). These data illustrate that exposure to low concentrations of S 47445 causes a rapid increase of potency of the AMPA receptors currents with no development of desensitization following several pulses of glutamate.
	Fig 6. Mean concentration-response to GYKI52466 in presence of 1 μM S 47445.Typical currents in a cell expressing are shown in the upper panel and concentration-response curve in the lower panel. These data show that of the potentiation effect of S 47445 observed at the concentration of 1 μM on the amplitude of the glutamate-evoked (10 μM) was reduced by the selective AMPA receptor antagonist GYKI52466 applied from the 10 μM concentration.
	Fig 7. Effects of GYKI52466 attenuates the potentiation caused by S 47445 but not the sensitivity.Determination of the potentiation caused by a series of S 47445 on the response evoked by 10 μM glutamate conducted in absence or presence of GYKI52466. Typical currents evoked by a 10 μM glutamate test pulse recorded in the same cell are illustrated in the inset. Currents were normalized to unity for the maximal value recorded in presence of 30 μM glutamate alone on the same oocytes (n = 3). Note that exposure to GYKI52466 caused a significant reduction of the magnitude of the potentiation but does not alter the sensitivity to S 47445.
	Fig 8. Effect of S 47445 at chimeric AMPA/kainate receptors.Typical examples of glutamate-evoked currents in absence and presence of 100 μM S 47445 obtained from the same oocyte expressing either GluA1flop (GluA1o) AMPA R receptors, GluK2 kainate Q editing form receptors or chimeric of AMPA/kainate receptors, GluA1(K2S1) or GluA1(K2NTD). Cells were held at -80 mV.
	Fig 9. Effect of S 47445 on cellular toxicity on rat primary cortical cell cultures.Cell mortality was estimated by measurement of lactate deshydrogenase (LDH) and was normalized as a percentage of the one measured with vehicle. (A) Intrinsic toxicity induced by S 47445 at 0.1, 3 and 10 μM (n = 4 independent cultures), (B) Rat primary cortical neurons were exposed to a concentration response of glutamate (0.03, 1, 3, 10, 20, 50, 75 and 100 μM) for 10 min ± S 47445 (0.1, 3 and 10 μM) (n = 4 independent cultures). * p≤0.05 S 47445 10 μM compared to vehicle group, ANOVA followed by Fisher’s Protected Least Significant Difference and (C) Effect of S 47445 (10 μM) in presence of a neutralizing BDNF antibody (BDNF Ab) on glutamate-induced neuronal damage. * p≤0.05S 47445 10 μM compared to vehicle group; # p≤0.05 BDNF Ab/S 47445 10 μM compared to S 47445 10 μM group.
	Fig 10. Effect of S 47445 in a novel object recognition task in rats (n = 10–11).Rats were treated p.o. either with S 47445 (0.3, 1 and 3 mg/kg) or vehicle, daily for 3 days i.e. 60 min before habituation, familiarisation and recognition phases. Histograms represent the mean ± SEM of the difference of the discrimination index during the recognition phase. * p≤0.05 and ** p≤0.01 versus vehicle group, one way ANOVA followed by a Dunnett’s test.
	Fig 11. Effect of S 47445 on spontaneous alternation in T-maze in mice (n = 12).Mice were treated i.p. with either S 47445 (0.1, 0.3 and 1 mg/kg) or vehicle, 30 min prior to the test. Histograms illustrate the mean ± SEM of the percentage of spontaneous alternation of mice. + p = 0.07 and * p≤0.05 versus vehicle group, one way ANOVA followed by a Dunnett’s test.
	Fig 12. Effect of S 47445 on spontaneous locomotor activity in rats and mice.(A) Effect of S 47445 (10, 30 and 100 mg/kg, p.o.) on spontaneous locomotor activity recorded for 30 min, 1 hour after acute administration in Wistar rats (n = 9). Covered distance (cm) was expressed as means + SEM over 3 successive periods of 10 min (0–10, 10–20 and 20–30 min) and overall (0–30 min). Result indicated in brackets represents the percentage of variation as compared to vehicle. (B and C) Effect of S 47445 (10, 30 and 100 mg/kg, p.o.) on spontaneous locomotor activity recorded for 30 min, 1 hour after acute administration in NMRI mice (n = 12). Global activity (B) was expressed as mean ± SEM and number of rearing (C) as median and interquartile range over 6 successive periods of 10 min (0–10, 10–20, 20–30, 30–40, 40–50 and 50–60 min).

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