Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

Abstract

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. What is not well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through selective expression of its receptor, GLP-1R. RNA-seq demonstrated that most Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1rires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study identifies a potential neurohormonal mechanism linking a critically important satiety signal with activity of MCs in the ventral DG that might have functional effects on learning and memory during distinct states.

Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice

“…In addition, enhanced MC→GC excitation may occur when tonic inhibition of GCs wanes at times during the estrous cycle (Maguire et al, 2005). Agonists of the glucagon-like peptide 1 receptor, involved in feeding, and oxytocin, involved in diverse social behaviors, excite MCs [(Steiner et al, 2022; Hung et al, 2023), but see (Harden and Frazier, 2016)]. Finally, activation of extrasynaptic kainate receptors drives hilar mossy cell activity (Ramos et al, 2022)…”

Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes

“…This response suggesting a functional reorganization in T2D was related to the levels of a neuroprotective neuropeptide which crosses the blood-brain-barrier, GLP-1. This neuropeptide is known to mediate direct neural effects in relation to memory functions [ 25 , 38 ]. Moreover, it does not change microvascular perfusion [ 25 ].…”

“…Accordingly, GLP-1 as neuropeptide, passes the blood brain barrier and has specific receptors, namely GLP-1R, in many cerebral regions, such as hippocampus, and more concretely in CA1 sub region [ 14 , 26 , 38 ]. Acute elevation of plasma GLP-1 levels as seen postprandially can rapidly act on various regions of the brain to exert neurobiological actions [ 25 ].…”