Glycine Two-way Plasticity Of Nmda Receptor Induced Current And Its Mechanism

Synaptic plasticity, which referring to the changes in effeciency of synaptictransmission in the event of experience, is considered to be an critical mechanismunderlying learning and memory.So far, long-term potentiation and long-term declineare the most deeply and widely investigated forms of synaptic plasticity.In the central nervous system （CNS）, plenty of amino acids can serve as excitatoryor inhibitory neurotransmitters, such as glutamate,γ-aminobutyric acid （GABA） andglycine were studied widely. In the adult animal brain, glutamate is the majorexcitatory neurotransmitter. GABA and glycine are the major inhibitoryneurotransmitters.In addition, glycine is co-agonist of N-methyl-D-aspartate receptor,which plays an important role in the excitatory glutamatergic synaptic transmission.Glycine in the hippocampus can exert its effect on both extrasynaptic functionalglycine receptors （GlyRs） and synaptic NMDA receptors （NMDARs） via distinctbinding sites located in these two receptors[1]. NMDA receptors （NMDARs） are notsimply anchored in the PSD. In fact, NMDARs-mediated synaptic expression couldchange on the membrane in a short time. Such as inserting or evacuating into synapticmembrane according to different activity of neuron. NR2A-containing NMDARs aretargeted to synaptic sites, while NR2B-containing NMDARs are mainly targeted toextrasynaptic sites. The surface mobility of NMDARs depends on the NR2subunit,that NR2B-containing NMDARs are more active than NR2A-containing ones.Previous studies of our lab have reported that low level glycine（0.6mM） can inducelong-term potentiation （LTP） of AMPA receptor through activation of NMDARs in hippocampal slices^[2].High level glycine（1.5mM） can induce long-term potentiation（LTD） of AMPA receptor through GlyR then regulating the activation of NMDARs.However, little is known about how the glycine regulating the NMDARs and themechanisms responsible for LTP and LTD of NMDA receptor （NMDAR）-mediatedEPSCs. Thus, we are interested that whether NMDARs are involved in and thenmediated the LTP/LTD by Glycine, and what are their mechanisms? In the presentstudies, using whole cell recording techniques we investigated the trafficking andexpression mechanisms underlying the LTP versus LTD of NMDAR-mediatedsynaptic responses in Schaffer-CA1synapses of hippocampal brain slice. In addition,we use the method of immunofluorescence to test this idea.We report here that glycine, no matter exogenously applied or endogenouslyreleased, can induce persistent dose-dependent bidirectional changes of（NMDAR）-mediated EPSCs responses in CA1neurons of hippocampal slices. Incontrast to glycine inducing LTP through activation of NMDARs at relative lowlevel（0.6mM）, glycine at high levels （1.5mM） induced long-term depression ofNMDARs(LTD_NMDA). GlyRs and NMDARs play key role in the changes of（NMDAR）-mediated EPSCs. Insertion of NMDARs are underlying glycine-inducedLTPNMDA, in sharp contrast, the glycine-induced LTD_NMDA is accompanied byinternalization of NMDA receptors （NMDARs）. Interestingly, we found thatNMDARs internalization through two distinct ways. On one hand, according toprevious studying[3], high level glycine can induce NMDARs internalization throughglycine binding-site of NMDARs. On other hand, we found that high level glycinecan active the GlyR to regulate the NMDARs.Finally, we found that LTPNMDA isinduced through PKC pathway, and LTD_NMDA is mainly because of the internalizationof NR2B-containing NMDARs. The results of this study suggest that the both exact application of glycine andprecise regulation of endogenous glycine may have critical physiological,pathological and clinical significance.Further more, our work completes the modelthat glycine can induce chemical bidirectional changes of AMPA EPSCs which builtby our lab previously. And this provide a new way to research the significant questionthat how the change of NMDARs regulates the change of AMPARs.