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. Glp1r-ires-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.

The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive compared to healthy controls. In rodent models of schizophrenia etiology, the ventral hippocampus, analogous to the human anterior hippocampus, is also hyperactive with effects on extrahippocampal neural circuits that might contribute to positive, negative, and cognitive symptoms. Less is known about how anterior hippocampal hyperactivity might directly influence intrahippocampal function across the structure’s longitudinal axis. This question is important for understanding cognitive dysfunction in schizophrenia, which includes deficits attributed to both the anterior and posterior hippocampus. We hypothesized that hyperactivity of ventral hippocampal mossy cells, which send dense longitudinal projections throughout the hippocampal longitudinal axis, may be sufficient to disrupt spatial memory encoding, a dorsal hippocampal-dependent function. Using an intersectional viral strategy, we targeted ventral mossy cells projecting to the dorsal dentate gyrus. In vivo fiber photometry revealed these cells were activated during behavior related to context mapping but not during non-exploratory motor behaviors. Anterograde transsynaptic tracing and optogenetic terminal stimulation revealed functional connectivity between ventral mossy cells and dorsal dentate gyrus granule cells. Finally, chemogenetic activation of ventral mossy cells during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. These findings suggest that anterior hippocampal hyperactivity may have intrahippocampal consequences to degrade posterior hippocampal function and support future studies engaging this circuit target to mitigate specific cognitive deficits associated with schizophrenia.

BACKGROUND: The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in many rodent models for schizophrenia risk. Mossy cells (MCs) of the ventral dentate gyrus (DG) densely project in the hippocampal long axis, targeting both dorsal DG granule cells and inhibitory interneurons. MCs are responsive to stimulation throughout hippocampal subfields and thus may be suited to detect hyperactivity in areas where it originates such as CA1. Here, we tested the hypothesis that hyperactivation of ventral MCs activates dorsal DG granule cells to influence dorsal hippocampal function. METHODS: In CD-1 mice, we targeted dorsal DG-projecting ventral MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral MCs was performed during exploratory behaviors. We used excitatory chemogenetic constructs to test the effects of ventral MC hyperactivation on longterm spatial memory during an object location memory task. RESULTS: Photometry revealed that ventral MCs were activated during exploratory rearing. Ventral MCs made functional monosynaptic inputs to dorsal DG granule cells, and chemogenetic activation of ventral MCs modestly increased activity of dorsal DG granule cells measured by c-Fos. Finally, chemogenetic activation of ventral MCs during the training phase of an object location memory task impaired test performance 24 hours later, without effects on locomotion or object exploration. CONCLUSIONS: These data suggest that ventral MC activation can directly excite dorsal granule cells and interfere with dorsal DG function, supporting future study of their in vivo activity in animal models for schizophrenia featuring ventral hyperactivity.