Presynaptic NMDARs facilitate GABA-mediated inhibition of pyramidal cells in mouse medial prefrontal cortex

PAFUNDO, DE; MIYAMAE T; LEWIS DA; GONZALEZ-BURGOS G

New Orleans, LA

Congreso; 42nd annual meeting of the Society for Neuroscience; 2012

Society for Neuroscience

N-methyl-D-aspartate receptor (NMDAR) antagonists administered systemically in vivo increase action potential firing in Pyramidal Cells (PCs). This effect of NMDAR antagonists, if linked to the NMDAR hypofunction hypothesis of schizophrenia, may contribute to the schizophrenia-like behavioral effects produced by NMDAR antagonist administration to control human subjects. The increase in PC firing with NMDAR antagonists suggests that the antagonists reduce GABA-mediated inhibition of PCs. Moreover, it was intially suggested that disinhibition occurs because parvalbumin-positive fast spiking (FS) GABA interneuron activation is strongly dependent on NMDAR stimulation by glutamate. However, several reports indicate that, in PFC circuits, the contribution of NMDARs to the synaptic activation of FS neurons is weaker than its contribution to excitation of PCs (i.e. FS neuron activation is less NMDAR dependent than PC excitation). Identifying cellular sites of action by which NMDARs could produce disinhibition is crucial to understanding their functional role in the PFC and in NMDAR hypofunction models of schizophrenia. Interestingly, recent studies show that in various types of synapses transmitter release is regulated by presynaptic NMDARs. Thus, presynaptic NMDARs may modulate synaptic transmission at inhibitory synaptic connections onto PFC PCs. To explore this possibility, we studied, in PCs of mouse medial PFC, inhibitory post synaptic currents (IPSCs) evoked by extracellular stimulation applied near the soma of the recorded neuron, thus mainly activating perisomatic GABA synapses. The NMDAR channel blocker MK801 (1 mM) added to the pipette solution completely blocked the NMDAR-mediated postsynaptic currents, showing that, in these conditions, manipulations of NMDAR activity can affect the recorded neuron only presynaptically. The amplitude of IPSCs evoked in layer 3 PCs was reversibly reduced 32 ± 5% (n=18) by application of the NMDAR antagonist APV (50 μM) and reversibly increased 32 ± 15% (n=12) after application of 10 μM NMDA. Consistent with a presynaptic effect, APV also changed the paired-pulse ratio (0.71 ± 0.05 to 0.81 ± 0.09; n=18). Similar results were obtained in experiments conducted in the presence of the N type Ca2+ channel blocker conotoxin GVIA, which blocks GABA release, and thus IPSCs, from cholecystokinin-positive interneurons (one of the two main subtypes of perisomatic-targeting interneurons) but does not affect IPSCs originating in FS cells. These results suggest that NMDARs facilitate release at GABA synapses onto PCs and that NMDAR antagonists may depress GABA synapses onto PCs by interfering with this mechanism.