Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex

doi:10.1016/j.biopsych.2018.01.018

Biological Psychiatry

Volume 84, Issue 6, 15 September 2018, Pages 460-470

https://doi.org/10.1016/j.biopsych.2018.01.018 Get rights and content

Abstract

Background

Testing hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist–mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Thus, if presynaptic NMDARs enhance gamma-aminobutyric acid release at PVBC-to-PC synapses, they could participate in NMDAR-dependent PC disinhibition. Here, we examined whether presynaptic NMDAR effects could modulate gamma-aminobutyric acid release at PVBC-to-PC synapses in mouse PFC.

Methods

Using whole-cell recordings from synaptically connected pairs in mouse PFC, we determined whether NMDA or NMDAR antagonist application affects PVBC-to-PC inhibition in a manner consistent with a presynaptic mechanism.

Results

NMDAR activation enhanced by ∼40% the synaptic current at PVBC-to-PC pairs. This effect was consistent with a presynaptic mechanism given that it was 1) observed with postsynaptic NMDARs blocked by intracellular MK801, 2) associated with a lower rate of transmission failures and a higher transmitter release probability, and 3) blocked by intracellular MK801 in the PVBC. NMDAR antagonist application did not affect the synaptic currents in PVBC-to-PC pairs, but it reduced the inhibitory currents elicited in PCs with simultaneous glutamate release by extracellular stimulation.

Conclusions

We demonstrate that NMDAR activation enhances PVBC-to-PC inhibition in a manner consistent with presynaptic mechanisms, and we suggest that the functional impact of this presynaptic effect depends on the activity state of the PFC network.

Section snippets

Animals and Slice Preparation

Experiments were performed in male and female G42 mice (Jackson Laboratory, Bar Harbor, ME), which express green fluorescent protein exclusively in PV⁺ neurons (32). Animals were deeply anesthetized with isoflurane following National Institutes of Health guidelines, as approved by the University of Pittsburgh Institutional Animal Care and Use Committee. Coronal brain slices (300-μm thick) were prepared from the frontal cortex of 27- to 66-day-old mice (mean = 39 days) using methods described

Results

We recorded IPSCs evoked in connected pairs of presynaptic PV⁺ neurons and postsynaptic PCs located in mid/deep layer 3 of the PFC of G42 mice, which express green fluorescent protein selectively in PV⁺ neurons 32, 37. All green fluorescent protein–positive cells in PFC layer 3 had fast-spiking phenotype and were basket cells (Figure 1A, B). No chandelier cells, which may be excitatory 38, 39, were found in layer 3. These findings are consistent with our recent study that PVBCs are present in

Discussion

We report that NMDAR activation enhances the strength of synaptic inhibition of PCs by PVBCs in layer 3 of mouse PFC via an effect apparently mediated by presynaptic changes at PVBC-to-PC synapses. This presynaptic NMDAR-mediated effect has important implications for the regulation of PFC network activity and for our understanding of how NMDAR antagonists, or NMDAR hypofunction, affect this activity.

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. MH51234 (to DAL) and P50MH103204 (to DAL, GG-B) and by Agencia Nacional de Promoción Científica y Técnológica Grant No. PICT-2016-0724 (to DEP).

We thank Olga L. Krimer for excellent technical assistance.

DAL currently receives investigator-initiated research support from Pfizer and recently served as a consultant to Sunovion in the areas of target identification and validation and new compound development. The other authors

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: DEP is currently affiliated with the Departamento de Fisiologia, Instituto de Fisiología y Biofísica Bernardo Houssay, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

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Archival ReportPresynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals and Slice Preparation

Results

Discussion

Acknowledgments and Disclosures

Neuropsychopharmacology

Biol Psychiatry

Biol Psychiatry

Neuron

Neuroscience

Trends Neurosci

Trends Pharmacol Sci

Neuron

Neuron

Neuron

Neuron

Neuron

Neuropharmacology

Brain Res

Neuron

Neuron

Neuron

Biol Psychiatry

Recent advances in the phencyclidine model of schizophrenia

Am J Psychiatry

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses

Arch Gen Psychiatry

The glutamatergic dysfunction hypothesis for schizophrenia

Harv Rev Psychiatry

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

J Neurosci

Cognitive dysfunction in schizophrenia: Convergence of gamma-aminobutyric acid and glutamate alterations

Arch Neurol

Fast-spiking, parvalbumin+ GABAergic interneurons: From cellular design to microcircuit function

Science

Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia

Neuropsychopharmacology

Pathological basis for deficient excitatory drive to cortical parvalbumin interneurons in schizophrenia

Am J Psychiatry

Postsynaptic glutamate receptors and integrative properties of fast-spiking interneurons in the rat neocortex

J Neurophysiol

Spike-timing-dependent plasticity of neocortical excitatory synapses on inhibitory interneurons depends on target cell type

J Neurosci

Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs

J Neurosci

Cell type-specific development of NMDA receptors in the interneurons of rat prefrontal cortex

Neuropsychopharmacology

Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: Relevance for schizophrenia

J Neurosci

Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity

PLoS One

Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity

Nat Neurosci

Input-specific learning rules at excitatory synapses onto hippocampal parvalbumin-expressing interneurons

J Physiol

Target-specific properties of thalamocortical synapses onto layer 4 of mouse primary visual cortex

J Neurosci

Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5

J Physiol

Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex

J Neurosci

GABAergic and pyramidal neurons of deep cortical layers directly receive and differently integrate callosal input

Cereb Cortex

NMDA-receptor regulation of substance P release from primary afferent nociceptors

Nature

NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity

Nat Neurosci

Archival Report
Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell–Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex

Fast-spiking, parvalbumin⁺ GABAergic interneurons: From cellular design to microcircuit function