Presynaptic Effects of NMDA in Cerebellar Purkinje Cells and Interneurons

Abstract

NMDA receptors (NMDARs) are generally believed to mediate exclusively postsynaptic effects at brain synapses. Here we searched for presynaptic effects of NMDA at inhibitory synapses in rat cerebellar slices. In Purkinje cells, application of NMDA enhanced the frequency of miniature IPSCs (mIPSCs) but not that of miniature EPSCs (mEPSCs). This increase in frequency was dependent on the external Mg2+ concentration. In basket and stellate cells, NMDA induced an even larger mIPSC frequency increase than in Purkinje cells, whereas mEPSCs were again not affected. Moreover, NMDA induced an inward current in both types of interneuron, which translated into a small depolarization (approximately 10 mV for 30 microM NMDA) under current-clamp conditions. In paired recordings of connected basket cell-Purkinje cell synapses, depolarizations of 10-30 mV applied to the basket cell soma enhanced the frequency of postsynaptic mIPSCs, suggesting that somatic depolarization was partially transmitted to the terminals in the presence of tetrodotoxin. However, this effect was small and unlikely to account fully for the effects of NMDA on mIPSCs. Consistent with a small number of dendritic NMDARs, evoked EPSCs in interneurons had a remarkably small NMDA component. Evoked IPSCs at interneuron-interneuron synapses were inhibited by NMDA, and the rate of failures was increased, indicating again a presynaptic site of action. We conclude that activation of NMDARs in interneurons exerts complex presynaptic effects, and that the corresponding receptors are most likely located in the axonal domain of the cell.

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

“…It is conceivable to speculate that activation of presynaptic NMDA receptors causes influx of Ca 2ϩ through the NMDA receptors into the central terminals of primary afferents and subsequent increase of glutamate release, as shown in hippocampal slices (75). The influx of Ca 2ϩ could come directly from the opening of NMDA receptors (76) and/or from voltage-gated calcium channels in response to depolarization due to the opening of NMDA receptors (77,78).…”

Enhancement of GABA Release through Endogenous Activation of Axonal GABAAReceptors in Juvenile Cerebellum

“…It must be stressed, however, that there is a significant coupling between somatodendritic and axonal compartments in MLIs, so that somatic depolarizations are partially transmitted to presynaptic terminals (Glitsch and Marty, 1999;Mejia-Gervacio et al, 2007). Thus, in this case, a presynaptic site of action does not necessarily imply that the receptors are located in the axonal compartment.…”

Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor

“…In addition, presynaptic actions of NMDA on interneurons have previously been demonstrated in rat cerebellar slices (Glitsch and Marty, 1999) and cultured cerebellar neurons (Fiszman et al, 2005), where chronic exposure to NMDA increased spontaneous transmitter release at GABAergic synapses by enhancing the size of GABAergic boutons along the axons of developing GABAergic interneurons. Similar presynaptic effects were reported for AMPA on interneurons in stellate cells from cerebellar slices (Bureau and Mulle, 1998).…”