Dendrodendritic Inhibition in the Olfactory Bulb Is Driven by NMDA Receptors

Abstract

At many central excitatory synapses, AMPA receptors relay the electrical signal, whereas activation of NMDA receptors is conditional and serves a modulatory function. We show here quite a different role for NMDA receptors at dendrodendritic synapses between mitral and granule cells in the rat olfactory bulb. In whole-cell patch-clamp recordings in bulb slices, stimulation of mitral cells elicited slowly decaying, GABA A receptor-mediated reciprocal IPSCs that reflected prolonged GABA release from granule cells. Although granule cells had a normal complement of AMPA and NMDA receptors, the IPSC was completely blocked by the NMDA receptor antagonist D,L-AP-5, suggesting that NMDA receptor activation is an absolute requirement for dendrodendritic inhibition. The AMPA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX) had no effect on IPSCs in the absence of extracellular magnesium but modestly reduced IPSCs in 1 mM magnesium, indicating that the primary effect of the AMPA receptor-mediated depolarization was to facilitate the unblocking of NMDA receptors. Granule cell voltage recordings indicated that effective spike stimulation in granule cells depended on the slow NMDA receptor kinetics. Granule cells also showed a pronounced delay between synaptic stimulation and action potential generation, suggesting that their intrinsic membrane properties underlie the ineffectiveness of brief AMPA receptor-mediated EPSPs. NMDA receptors also seem to have a central role in dendrodendritic inhibition in vivo, because intraperitoneal dizocilpine maleate (MK-801) injection in young adult rats resulted in disinhibition of mitral cells as measured by the generation of c-fos mRNA. The unique dependence of dendrodendritic inhibition on slow EPSPs generated by NMDA receptors suggests that olfactory information processing depends on long-lasting reciprocal and lateral inhibition.

Organization of Ionotropic Glutamate Receptors at Dendrodendritic Synapses in the Rat Olfactory Bulb

“…This is consistent with the electrophysiological results of Schoppa et al (1998), who analyzed miniature EPSCs in granule cells. However, these results leave open the possibility that a small number of dendrodendritic synapses contain NMDA receptors but not AMPA receptors (an even smaller number could be endowed with the complementary receptor profile).…”

“…It has been shown that dendrodendritic synapses possess unique functional properties, such as a dependence on NMDA receptors rather than AMPA receptors for their activation (Isaacson and Strowbridge, 1998;Schoppa et al, 1998). Here, we have shown that NMDA and AMPA receptors are colocalized at dendrodendritic synapses and that they are distributed along the entire postsynaptic specialization of granule cell spines.…”

“…These studies have demonstrated that mitral cells release glutamate and excite granule cell dendrites (Trombley and Shepherd, 1992;Wellis and Kauer, 1994), which in turn mediate GABAergic inhibition back onto the mitral cells (Nicoll, 1971;Nowycky et al, 1981a;Jahr and Nicoll, 1982;Wellis and Kauer, 1993). Recent electrophysiological investigations have revealed unexpected properties of dendrodendritic synapses, including a dependence on NMDA, rather than AMPA, receptors for the activation of granule cells (Isaacson and Strowbridge, 1998;Schoppa et al, 1998) and a self-excitation of mitral cell dendrites, similarly dependent on NMDA receptors (Aroniadou-Anderjaska et al, 1999;Isaacson, 1999). Based on these observations, one would hypothesize that NMDA receptors are located presynaptically as well as postsynaptically at dendrodendritic synapses, but this remains to be shown by anatomical techniques.…”

“…Likewise, it is not known whether NMDA and AMPA receptors differ in their distance from the presynaptic active zones, which could explain why AMPA receptors are less effective than NMDA receptors at eliciting GABA release from granule cells. The specialized arrangement of reciprocal synapses also suggests that NMDA receptors could be located close to the GABA release sites on granule cell dendrites and that entry of calcium through these receptors could contribute to trigger the release of GABA (see Discussion in Isaacson and Strowbridge, 1998;Schoppa et al, 1998).…”

α2-Adrenergic receptor activation promotes long-term potentiation at excitatory synapses in the mouse accessory olfactory bulb

“…Conventional whole-cell recordings with Cs + -internal solution in the pipette were performed in the presence of TTX (1 µM) to block Na + channels and thus prevent any contribution of axonal transmission. A depolarizing voltage step reported to evoke a relatively slow inward Ca 2+ current (Isaacson and Strowbridge 1998;Schoppa et al 1998;Taniguchi and Kaba 2001;Castro et al 2007) was followed by IPSCs (Fig. 5A).…”