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Group I metabotropic glutamate receptors differentially modulate excitatory transmission across interneuron types in

Joanna Grace Sandle^1,2, Gábor Molnár¹, Martin Tóth¹

¹HUN-REN-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary.

Frontiers in Synaptic Neuroscience

|March 2, 2026

Abstract

Introduction:

Group I metabotropic glutamate receptors (mGluRs) play a critical role in regulating neuronal excitability, synaptic strength, and cortical network activity. Although their physiological functions and involvement in neurological disorders are well established, direct experimental evidence for their role in human cortical neurons remains limited.

Methods:

We investigated the effects of group I mGluR activation on excitatory synaptic transmission in the human supragranular cortex using paired whole-cell patch-clamp recordings from synaptically connected pyramidal cells and interneurons in acute slices of human neocortex resected during neurosurgery.

Results:

Activation of mGluRs with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) altered excitatory synaptic efficacy in an interneuron subtype-dependent manner. Specifically, we observed acute enhancement of excitatory postsynaptic current (EPSC) amplitudes in 54% of fast-spiking interneurons and in 15% of non-fast-spiking interneuron types. Applying the same experimental protocol in slices from Wistar rats resulted in a similar increase in synaptic strength in fast-spiking interneurons. However, paired-pulse ratio analysis showed species-dependent differences, which may reflect distinct contributions of pre- and postsynaptic factors to the observed modulation.

Discussion:

Together, these results demonstrate that acute modulation of pyramidal cell-fast-spiking interneuron synapses via group I mGluRs is conserved between human and rodent neocortex, while pointing to species-specific underlying mechanisms. Moreover, mGluR-mediated modulation exhibits cell-type specificity in human cortical circuits. Collectively, these findings provide direct functional evidence for group I mGluR-dependent synaptic regulation in the human cortex and highlight important species- and cell-type-specific differences that should be considered when extrapolating rodent data to human cortical physiology and disease mechanisms.

Keywords:

brain slice electrophysiology fast-spiking interneurons human neocortex interneurons synaptic modulation type I metabotropic glutamate receptors

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