NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons

Abstract

NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.

Figure 1.

Distinction between putative interneurons (FS units) and pyramidal neurons (RS units). A, The population of putative interneurons had a higher firing rate (abscissa) and narrower spikeform (ordinate, average ± SEM of peak to valley spike width). B, Average waveforms of representative RS and FS units. C, Superimposed composite of all the waveforms for the same units. D, Superimposed average waveforms during two 10 min windows, pre- and post-MK801 administration. The waveforms remained stable after MK801 treatment compared with the predrug period.

Figure 2.

Inhibitory effects of MK801 on putative interneurons. A, B, Examples of inhibitory and excitatory effects of MK801 on an individual interneuron (A) and a pyramidal neuron (B). Each panel depicts the firing rate histogram (bin, 1 min; smoothed with a Gaussian filter with bin width of 3) of a single unit. Arrow indicates the time of MK801 injection. C, Distribution of firing rate responses (increase, decrease, or no change) to MK801 was significantly different among populations of RS and FS units (*p < 0.001). D, Comparison of average population response of RS and FS units to MK801. Two-way ANOVA with time as the repeated measure revealed a significant effect for neuron type (F_(1,259) = 12.96; p < 0.001), time (F_(59,15281) = 2.71; p < 0.001), and type by time interaction (F_(59,15281) = 5.94; p < 0.001). The averages for all FS units and those with a decreased response type have been depicted as dashed and solid gray lines, respectively.

Figure 3.

MK801 inhibition of interneurons precedes its excitation of pyramidal cells. A, Superimposed firing-rate histogram of simultaneously recorded pairs of interneurons (bar graph) and pyramidal neurons (solid line). Arrow indicates the time of MK801 injection. Bin size, 1 min. B, Normalized firing rate histogram of another pair of simultaneously recorded interneuron (bar graph; baseline firing rate, 17.26 Hz) and pyramidal neuron (solid line; baseline, 2.86 Hz). Inset, Finer timescale with 20 s bins. C, D, Putative interneurons preceded their concurrently recorded pyramidal neurons both in the onset of their inhibition (C) and in reaching the inhibitory plateau (D). Each dot in the scatter plots depicts the post-MK801 delay to onset (C) or plateau (D) of inhibitory response for interneuron/s recorded during a single session versus the delay to onset (C) or plateau (D) of excitatory response for the average pyramidal neurons in the same session. A dashed line indicates no change from baseline and a solid line depicts the linear regression. Inset, Median and 95% confidence intervals of the difference in the delay between inhibitory versus excitatory response onset (C) or plateau (D), with a positive value indicating inhibition preceding the excitation (y-axis range, 0–1500 s).