Ionic and Signaling Mechanisms Involved in the Excitation of Entorhinal Neurons by Group I mGluRs

Neuropharmacology. 2025 Sep 11:110683. doi: 10.1016/j.neuropharm.2025.110683. Online ahead of print.

ABSTRACT

Activation of metabotropic glutamate receptors (mGluRs) modulates neuronal excitability, synaptic transmission and plasticity in the brain. While group I mGluRs in layer III pyramidal neurons in the entorhinal cortex (EC) are implicated in persistent firing which is considered as a cellular mechanism for working memory, the underlying ionic and signaling mechanisms have not been determined. Here, we showed that application of (S)-3,5-dihydroxyphenylglycine (DHPG), the selective agonist for group I mGluRs, excited layer III pyramidal neurons of the EC via activation of both mGluR1 and mGluR5. DHPG excited layer III pyramidal neurons by activating TRPC5 channels and depressing GIRK type of inwardly rectifying K⁺ (Kir) channels. The functions of G proteins, phospholipase Cβ (PLCβ) and PLCβ-mediated depletion of PIP₂ were required for group I mGluR-mediated activation of TRPC5 and depression of GIRK channels, whereas intracellular Ca²⁺ release and PKC were not involved in DHPG-elicited excitation of layer III pyramidal neurons. We also found that diacylglycerol was involved in DHPG-elicited activation of TRPC5 channels. Our results may serve as a signaling and ionic mechanism to explain the physiological functions of group I mGluRs in vivo.

PMID:40945901 | DOI:10.1016/j.neuropharm.2025.110683