Nonpathological aging is associated with variable cognitive decline that may be ascribed to changes in the ability of hippocampal neurons to encode information. Thus far, most attention has been focused on area CA1 of the hippocampus (Brahimi et al., 2023, Markham et al., 2005, Shankar et al., 1998). However, the intrinsic and synaptic properties of area CA3 are crucial for the higher cognitive functions linked to this brain structure, which are often compromised in older animals and individuals (Simic et al., 1997, Yassa et al., 2011). For instance, dentate gyrus (DG) mossy fiber (MF) inputs to CA3 pyramidal cells (CA3 PCs) constitute the major source of excitation to the hippocampus (Henze et al., 2000), and CA3-CA3 recurrent connections have been suggested to be the neurobiological substrate of pattern completion, a neuronal computation that underlies the recalling of complex experiences (Ngo et al., 2021, Rolls, 2013). Some studies have reported age-related adaptations in the morphological and electrophysiological properties of CA3 PCs, including enhanced excitability (Simkin et al., 2015, Wilson et al., 2005), changes in dendritic spines (Aguilar-Hernandez et al., 2020) and impairments in different forms of synaptic plasticity (Maglione et al., 2019, Villanueva-Castillo et al., 2017, Yang et al., 2013).

On the other hand, a prominent feature of aging is the dysregulation of G protein-coupled receptors (GPCRs) (de Oliveira et al., 2019). In this sense, metabotropic glutamate receptors (mGluRs) are a group of GPCRs that exert a wide array of modulatory actions, including the fine-tuning of intrinsic excitability, modulation of the synaptic transmission, and control of multiple forms of long-term plasticity (Brager and Johnston, 2007, Cosgrove et al., 2011, Kelly et al., 2009, Samadi et al., 2023). Whereas pharmacological stimulation of Group I mGluRs increases the excitability of CA3 PCs (Young et al., 2008, Young et al., 2013) activation of Group II and III mGluR weakens the glutamatergic transmission and triggers forms of long-term synaptic depression in the DG-CA3 circuit (Cosgrove et al., 2011, Manzoni et al., 1995, Pelkey et al., 2005). Previous studies have documented several changes in the expression of mGluRs associated with aging (Hernandez et al., 2018, Simonyi et al., 2000). Given the critical role of mGluRs in the regulation of synaptic plasticity and neuronal communication, the altered expression or activity of these receptors may lead to impairments in cognitive capabilities. This study used cellular electrophysiology and pharmacological tools to examine the impact of nonpathological aging on the mGluR-mediated cellular excitability and synaptic transmission in the synapse formed by the DG MFs, on CA3 PCs.