NMDA receptor activation enhances inhibitory GABAergic transmission onto hippocampal pyramidal neurons via presynaptic and postsynaptic mechanisms

Abstract

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABA(A) receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.

NO regulates the strength of synaptic inputs onto hippocampal CA1 neurons via NO-GC1/cGMP signalling

“…To decrease the leakage of MK-801 from the recording pipette, the tip was filled with normal intracellular solution and backfilled with MK-801-containg solution, and only low positive pressure was used when approaching the cell. The block of NMDAR activity by intracellular application of MK-801 is a well-established approach and has been used by others before [2,10,30,32] and in our own lab [31]. We observed a significant reduction of the mean sIPSC frequency in WT neurons, whereas NO-GC1KO pyramidal neurons remained completely unaffected.…”

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

“…NMDARs are mostly postsynaptic in the hippocampus (Nyiri et al, 2003;Takumi et al, 1999), and have a greater expression of NR2B subunits than other NMDA subunits (ie, NR2A) in the CA1 subregion, but not in the CA3 subregion or the dentate gyrus (Coultrap et al, 2005;Pandis et al, 2006). Also, within the CA1 subregion, NMDAR subunit composition and density vary across cell types (Angulo et al, 2004;Nyiri et al, 2003;Serrano et al, 2006;Serrano et al, 2008;Siegel et al, 1994;Szabadits et al, 2011;Todd et al, 2006;Xue et al, 2011). Thus, given the functional heterogeneity of hippocampal NMDAR populations (Kesner, 2007;Lee et al, 2003), future studies will be necessary to dissect the role of distinct NR2B subunitcontaining NMDAR subpopulations within the DH in drug context-induced cocaine-seeking behavior.…”

Bidirectional plasticity in striatonigral synapses: A switch to balance direct and indirect basal ganglia pathways

“…Finally, substantial evidence supporting presynaptic modulation of nigral afferents by both D 1 and CB 1 receptors (Szabo et al 2000;Yanovsky et al 2003;Misgeld et al 2007;Aceves et al 2011) makes inferable that long-term plastic changes may be mediated, modulated, or triggered by these receptors and their associated signaling. Possible mechanisms associated with cannabinergic actions have to be investigated in future studies (e.g., Mulkey et al 1994;Iribe et al 1999;Massey and Bashir 2007;Szabadits et al 2011;Xue et al 2011).…”

“…It was observed that AM-251 could not reverse the already installed depression (Fig. 3D, gray bar), suggesting, as the most parsimonious working hypothesis, that this HFS-induced depression is a true long-term depression (LTD) (e.g., Mulkey et al 1994;Gerdeman and Lovinger 2003;Hashimotodani et al 2005;Massey and Bashir 2007;Sergeeva et al 2007;Szabadits et al 2011;Xue et al 2011) in need of further exploration. Because once-established time courses with and without AM-251 were similar, all data were pooled together in the time courses illustrated in Figure 3D.…”

“…A significant IPSC facilitation was not produced in this situation either (negative results not shown). Striatonigral facilitation could only be produced when NMDA receptors were blocked, perhaps due to a mixture of inhibitory polysynaptic influences onto dopamine neurons (Iribe et al 1999), the action of D 2 -dopamine receptors on dopamine neurons (Giuffrida et al 1999), or subsequent signaling cascades or receptors set into action after NMDA-receptors activation (Mulkey et al 1994;Hashimotodani et al 2005;Massey and Bashir 2007;Sergeeva et al 2007;Szabadits et al 2011;Xue et al 2011). These alternative routes are left for future investigation and are out of the scope of the present report; even for the corticostriatal synapse, some of these signaling pathways are still under debate (Surmeier et al 2009;Wickens 2009).…”