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Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level

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Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level ARTICLE Received 23 Jan 2013 | Accepted 21 Mar 2013 | Published 23 Apr 2013 DOI: 10.1038/ncomms2779 Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level Yan Li 1, Silvia Sacchi2, Loredano Pollegioni2, Alo C. Basu1, Joseph T. Coyle1 & Vadim Y. Bolshakov1 Mechanisms of N-methyl-D-aspartate receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of N-methyl-D-aspartate receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the N-methyl-D-aspartate receptor glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of N-methyl- D-aspartate receptors at synapses in the amygdala under low activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced N-methyl-D-aspartate receptor-mediated synaptic events, serving an essential function in the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation in fear conditioning pathways. 1 Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA. 2 Department of Biotechnology and Molecular Sciences, University of Insubria, ‘The Protein Factory’ Research Center for Protein Biotechnologies, Politecnico di Milano and University of Insubria, Varese 21100, Italy. Correspondence and requests for materials should be addressed to V.Y.B. (email: [email protected]). NATURE COMMUNICATIONS | 4:1760 | DOI: 10.1038/ncomms2779 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms2779 þ ctivation of N-methyl-D-aspartate receptors (NMDARs) increases in the intra-astrocyte Na concentration, possibly by glutamate in the brain defines many crucial biological due to activation of astrocytic a-amino-3-hydroxy-5-methyl-4- 13–15 Aprocesses, including learning, memory and developmental isoxazolepropionic acid (AMPA) receptors . D-serine can also plasticity1,2. Unlike other neurotransmitter receptors, activation be released from astrocytes via mechanisms implicating Ca2 þ and of NMDARs requires simultaneous occupation of two different SNARE-dependent exocytosis10,12,16 (but see Agulhon et al.17)or binding sites by glutamate and the glycine site agonist, from neurons18 via a nonvesicular release mechanism19. respectively3–5. Previous experimental findings provided Whereas the results of earlier experiments suggested that 6–8 9–12 evidence for the role of either glycine or D-serine as the tonically present glycine could saturate the NMDA receptor endogenous NMDAR glycine site agonist at central synapses. glycine site20, it has been shown in subsequent studies that Glycine may be accumulated by astrocytes, expressing the glycine glycine transporters decrease the concentration of glycine at transporter GlyT1, and could be released by them through synaptic sites below the saturation level6,7,21. Consistent with the the mechanisms of reverse transport in response to the local latter finding, it has been demonstrated that the degree of Vh = +40 mV Vh = –70 mV Spontaneous release 12 *** *** Control DAAO DAAO + D-ser D-ser 6 l (pA) *** +40 mV 0 –70 mV –6 10 pA 20 ms sEPSC amp –12 -ser -ser D DAAO DAAOD Control + 12 *** Control GO GO + Gly Gly ** l (pA) 6 +40 mV 0 –70 mV –6 10 pA sEPSC amp –12 GO Gly Control GO+Gly Evoked release 0.6 Control DAAO DAAO + D-ser 0.4 +40 mV AMPA ratio 0.2 –70 mV 0 100 pA 100 pA 100 pA NMDA/ 40 ms Control DAAO DAAO +D-ser Control GO GO + Gly 0.6 +40 mV 0.4 –70 mV AMPA ratio 0.2 ** 100 pA 100 pA 100 pA 0 NMDA/ GO Control GO + Gly Figure 1 | D-serine supports tonic NMDAR activation and glycine serves as the glycine site agonist during afferent stimulation. (a) Averaged sEPSCs (50–100 events) recorded from LA neurons at À 70 mV or þ 40 mV under control conditions, following treatment of slices with DAAO (45 min; 1 0.17 unit ml À ), and after addition of D-serine (10 mM) to treated or control slices. NMDAR-mediated component was measured at þ 40 mV (dashed lines). (b) Summary of experiments as in a. Control, n ¼ 9 neurons; DAAO, n ¼ 10; DAAO þ D-serine, n ¼ 8; D-serine alone, n ¼ 10. NMDAR current was decreased following the treatment (t-test, ***Po0.001 versus control). NMDAR current was potentiated in the DAAO þ D-serine or control D-serine groups (***Po0.001). P ¼ 0.6 between DAAO þ D-serine and D-serine only groups. AMPAR EPSCs at À 70 mV remained unchanged. (c) Slices were treated with GO (45 min; 0.04 unit ml À 1) and glycine (10 mM) was applied after the treatment or under control conditions. (d) Summary of experiments as in c. Control, n ¼ 7 neurons; GO, n ¼ 14; GO þ glycine, n ¼ 9; glycine alone, n ¼ 5. P ¼ 0.62 for GO versus control, **P ¼ 0.004 for control versus GO þ glycine, t-test. P ¼ 0.06 between GO þ glycine and glycine only groups. ***Po0.001 for glycine alone versus control. (e) Averaged traces (15 responses) of evoked thalamo-LA EPSCs recorded at À 70 mV and þ 40 mV under three conditions: control, after DAAO treatment and after addition of D-serine (10 mM) to DAAO-treated slices. (f) Summary plot of the NMDA/AMPA amplitude ratios for experiments as in e. Control, n ¼ 10 neurons; DAAO, n ¼ 11; DAAO þ D-serine, n ¼ 6. P ¼ 0.8 for control versus DAAO group; P ¼ 0.55 for DAAO versus DAAO þ D-serine, t-test. (g) Slices were treated with GO. (h) Summary of experiments as in g. NMDA/AMPA ratio: control, n ¼ 13 neurons; GO, n ¼ 12; GO þ glycine, n ¼ 6. **P ¼ 0.002 for control versus GO group, t-test. P ¼ 0.16 for control versus GO þ glycine. Error bars are s.e.m. 2 NATURE COMMUNICATIONS | 4:1760 | DOI: 10.1038/ncomms2779 | www.nature.com/naturecommunications & 2013 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms2779 ARTICLE NMDAR activation could be regulated through the changes in the performing high-performance liquid chromatography (HPLC) 8,22 glycine site occupancy . The lack of the glycine site saturation, analysis. In these experiments, D-serine and glycine were however, is not universal, as the glycine site was shown to be detected in the external solution which was bathing slices for saturated by endogenous coagonist at the cerebellar mossy fibres 45 min. We found that concentrations of D-serine or glycine to granule cell synapses23. This indicates that the level of the decreased significantly in slices treated for 45 min with DAAO glycine site occupancy by the coagonist under baseline conditions (0.17 U ml À 1) or GO (0.04 U ml À 1), respectively (Supplementary might reflect characteristics of particular synaptic connections. Fig. S2). The effects of treatments on D-serine or glycine were Notably, there is evidence that the NMDAR glycine site might be enzyme specific, as DAAO degraded D-serine but not glycine, unsaturated at central synapses in vivo24,25, indicating that the whereas GO reduced glycine concentration but had no effect on results on modulation of the NMDARs in acute brain slices could D-serine. These results provide evidence that enzymes were, in be extrapolated to the certain degree to the in vivo situation. fact, degrading D-serine or glycine in our experiments. Little is known, however, about the most fundamental aspects The decreases in the amplitude of spontaneous miniature of NMDAR function in the amygdala, a key brain structure in NMDAR-mediated currents (mEPSCs) were also observed when fear-related behaviours26,27. This is an important issue as the DAAO was applied in the presence of the Na þ channel blocker acquisition of conditioned fear, resulting from a formation of the tetrodotoxin (TTX, 1 mM), suppressing spontaneous network association between conditioned and unconditioned stimuli (CS activity (Supplementary Fig. S3). It indicates that ambient 28–30 and US, respectively), is NMDAR dependent and implicates D-serine, but not glycine, maintains synaptic activation of the mechanisms of NMDA receptor-dependent plasticity in the NMDARs in LA neurons under resting or low activity conditions. CS pathways31–37. Surprisingly, the identity of the endogenous NMDA receptor glycine site agonist in amygdala remains undetermined. Another fundamental question, which has not Synaptic activity defines identity of glycine site agonist. Next, been addressed in any region of the brain, is whether the identity we recorded evoked synaptic currents in thalamic projections to of the coagonist is unchanged while signals propagate within the the LA39, induced repetitively by single presynaptic stimuli at a neuronal network or it might be related to the afferent activity stimulation frequency of 0.1 Hz delivered to the internal capsule patterns. We addressed these questions by studying the in the brain slices36. The NMDAR-mediated synaptic current mechanisms of NMDAR activation under different degrees of component was measured 40 ms after the peak of AMPAR afferent activity. We found that the identity of the NMDAR EPSCs (assayed at À 70 mV) at þ 40 mV, thus minimizing a glycine site agonist at synapses in the lateral nucleus of the contamination by the AMPAR-mediated synaptic current40 amygdala (LA), glycine or D-serine, is determined by the level (Supplementary Fig. S4). Unexpectedly, the NMDA/AMPA of synaptic activity, affecting the inducibility of long-term amplitude ratio of the averaged evoked EPSCs, which provides potentiation (LTP) in the auditory CS pathways.
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