Group I mGluR-Mediated Activation of Martinotti Cells Inhibits Local Cortical Circuitry in Human Cortex.

Tim Kroon,Julia Dawitz,René Wilbers,Johannes C Baayen,Eleonora Aronica,Sander Idema,Ioannis Kramvis,Natalia A Goriounova,Jasper Anink,Huibert D Mansvelder,Matthijs B Verhoog,Rhiannon M Meredith,Joshua Obermayer

doi:10.3389/fncel.2019.00315

Abstract

Group I metabotropic glutamate receptors (mGluRs) mediate a range of signaling and plasticity processes in the brain and are of growing importance as potential therapeutic targets in clinical trials for neuropsychiatric and neurodevelopmental disorders (NDDs). Fundamental knowledge regarding the functional effects of mGluRs upon pyramidal neurons and interneurons is derived largely from rodent brain, and their effects upon human neurons are predominantly untested. We therefore addressed how group I mGluRs affect microcircuits in human neocortex. We show that activation of group I mGluRs elicits action potential firing in Martinotti cells, which leads to increased synaptic inhibition onto neighboring neurons. Some other interneurons, including fast-spiking interneurons, are depolarized but do not fire action potentials in response to group I mGluR activation. Furthermore, we confirm the existence of group I mGluR-mediated depression of excitatory synapses in human pyramidal neurons. We propose that the strong increase in inhibition and depression of excitatory synapses onto layer 2/3 pyramidal neurons upon group I mGluR activation likely results in a shift in the balance between excitation and inhibition in the human cortical network.

Highlights

Metabotropic glutamate receptors form a diverse set of G-protein-coupled receptors that are divided into three groups, based on sequence homology, pharmacological properties, and signal transduction (Nakanishi, 1992)
Activation of group I metabotropic glutamate receptors (mGluRs) increases spontaneous inhibition in rodent cortex (Paluszkiewicz et al, 2011b). To test whether this holds true in human cortex, we recorded spontaneous inhibitory postsynaptic currents in pyramidal neurons in layer 2/3 of surgically resected human neocortex and activated group I mGluRs by a 5-min bath application of the agonist (S)-3,5Dihydroxyphenylglycine (DHPG; Figures 1A–C)
As inputs that are further away from the soma appear to have slower kinetics due to the filtering properties of dendrites (Magee, 2000), we mGluRs Modulate Inhibition in Human Cortex hypothesized that the slower synaptic inputs elicited by DHPG might be onto distal dendrites and were likely coming from Martinotti cells (MCs)

Summary

Introduction

Metabotropic glutamate receptors (mGluRs) form a diverse set of G-protein-coupled receptors that are divided into three groups, based on sequence homology, pharmacological properties, and signal transduction (Nakanishi, 1992). Group I mGluRs are located perisynaptically and are involved in a range of signaling and synaptic plasticity processes (Luján et al, 1996) They are known for inducing a form of long-term depression (LTD) at glutamatergic synapses, which can be mediated by either mGluR1 or mGluR5, depending on brain region, postsynaptic cell type, and specific pathways in which the synapse is involved (Lüscher and Huber, 2010; Sherman, 2014). Activation of group I mGluRs can synchronize network activity by eliciting synchronous spiking in low-threshold spiking interneurons (Beierlein et al, 2000), which include Martinotti cells

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Results

Conclusion