Metabotropic Glutamate Receptors Differentially Regulate GABAergic Inhibition in Thalamus

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Abstract
Thalamic interneurons and thalamic reticular nucleus (TRN) neurons provide inhibitory innervation of thalamocortical cells that significantly influence thalamic gating. The local interneurons in the dorsal lateral geniculate nucleus (dLGN) give rise to two distinct synaptic outputs: classical axonal and dendrodendritic. Activation of metabotropic glutamate receptors (mGluRs) by agonists or optic tract stimulation increases the output of these presynaptic dendrites leading to increased inhibition of thalamocortical neurons. The present study was aimed to evaluate the actions of specific mGluRs on inhibitory GABA-mediated signaling. We found that the group I mGluR (mGluR1,5) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) or optic tract stimulation produced a robust increase in spontaneous IPSCs (sIPSCs) in thalamocortical neurons that was attenuated by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In contrast, the group II mGluR (mGluR2,3) agonists (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or (2S,2′R,3′R)-2-(2′3′-dicarboxycyclopropyl)glycine (DCG-IV) suppressed the frequency of sIPSCs. In addition, mGluR1,5 agonist DHPG produced depolarizations and mGluR2/3 agonists APDC or L-CCG-I [(2S,1′S,2′S)-2-(carboxycyclopropyl)glycine] produced hyperpolarizations in dLGN interneurons. Furthermore, the enhanced sIPSC activity by optic tract stimulation was reduced when paired with corticothalamic fiber stimulation. The present data indicate that activation of specific mGluR subtypes differentially regulates inhibitory activity via different synaptic pathways. Our results suggest that activation of specific mGluR subtypes can upregulate or downregulate inhibitory activity in thalamic relay neurons, and these actions likely shape excitatory synaptic integration and thus regulate information transfer through thalamocortical circuits.