Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

Abstract

Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long‐range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre‐dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2‐Cre) and calcitonin receptor‐like receptor (Crlr‐Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long‐range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal–ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal–ventral differences in DG function.

Flexible encoding of objects and space in single cells of the dentate gyrus

“…These types of studies may also reveal influences of the anatomical and functional gradients along the dorsoventral DG axis that are frequently overlooked in studies of DG spatial activity. 51,[64][65][66][67][68][69] Given that the effects of novel object exploration on mossy cell activity are more pronounced in the ventral than dorsal DG, 51,64 there may be a gradient of conjunctive object/space coding in which object information in dorsal DG is strongly tied to defined spatial firing locations, whereas ventral DG activity is less spatially modulated and more sensitive to object novelty. Furthermore, the DG contains a diverse population of interneurons 70,71 that regulates activity throughout the DG, and their role in shaping object-related DG activity will require further study and analysis.…”

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

“…Gene expression of the receptors for ghrelin, insulin, and leptin, which like GLP-1 are other feeding-relevant hormones previously shown to be important in hippocampal function (Suarez et al, 2019), was markedly lower than Glp1r expression and not enriched in MCs ( Figure 1b ). HippoSeq did not divide MCs into dorsal and ventral DG MCs, which is important because dorsal and ventral MCs differ not only molecularly (Blasco-Ibanez & Freund, 1997; Fujise, Liu, Hori, & Kosaka, 1998), physiologically (Bui et al, 2018; Fredes et al, 2021; Jinno, Ishizuka, & Kosaka, 2003), and anatomically (Botterill, Gerencer, Vinod, Alcantara-Gonzalez, & Scharfman, 2021; Houser, Peng, Wei, Huang, & Mody, 2020), but also in their role in cognitive function (Bauer et al, 2021; Botterill, Vinod, et al, 2021; Yassa & Stark, 2011). Therefore, to corroborate RNA-seq data and examine potential dorsal and ventral MC expression differences, we examined in situ hybridization (ISH) data for Glp1r from the Allen Mouse Brain Atlas (Lein et al, 2007) ( Figure 1c,d ).…”

“…As is the case for the hippocampal formation as a whole (Fanselow & Dong, 2010; Strange, Witter, Lein, & Moser, 2014), an appreciation of meaningful differences between dorsal and ventral DG MCs continues to evolve. These include marked differences in protein expression (Blasco-Ibanez & Freund, 1997; Cembrowski et al, 2016; Fujise et al, 1998), activity (Bui et al, 2018; Fredes et al, 2021; Jinno et al, 2003), connectivity (Botterill, Gerencer, et al, 2021; Houser et al, 2020), and effects on cognitive and behavioral function (Bauer et al, 2021; Botterill, Vinod, et al, 2021; Yassa & Stark, 2011). For instance, relevant to our Glp1r expression findings, in mice the calcium binding protein calretinin is strongly and selectively expressed in MCs in the ventral and intermediate DG whereas most dorsal MCs are calretinin-negative (Blasco-Ibanez & Freund, 1997; Fujise et al, 1998).…”

Activin A regulates the excitability of hippocampal mossy cells

“…It is worth noting that the expression of dnActRIB was driven by the CaMKIIα promotor (Müller et al, 2006). Thus, according to the expression pattern of CaMKIIα in the DG (Botterill, Gerencer, et al, 2021), the mutant activin receptor which precludes downstream signaling should be expressed only in excitatory neurons including MCs, but not in GABAergic interneurons, which should be endowed with functional ActRIB. The latter notion was confirmed by the fact that the dampening effect of recombinant activin on interneuron firing was not different between wild type and mutant mice.…”