Novelty and Novel Objects Increase c-Fos Immunoreactivity in Mossy Cells in the Mouse Dentate Gyrus.

The dentate gyrus (DG) and its primary cell type, the granule cell (GC), are thought to be critical to many cognitive functions. A major neuronal subtype of the DG is the hilar mossy cell (MC). MCs have been considered to play an important role in cognition, but in vivo studies to understand the activity of MCs during cognitive tasks are challenging because the experiments usually involve trauma to the overlying hippocampus or DG, which kills hilar neurons. In addition, restraint typically occurs, and MC activity is reduced by brief restraint stress. Social isolation often occurs and is potentially confounding. Therefore, we used c-fos protein expression to understand when MCs are active in vivo in socially housed adult C57BL/6 mice in their home cage. We focused on c-fos protein expression after animals explored novel objects, based on previous work which showed that MCs express c-fos protein readily in response to a novel housing location. Also, MCs are required for the training component of the novel object location task and novelty-encoding during a food-related task. GluR2/3 was used as a marker of MCs. The results showed that MC c-fos protein is greatly increased after exposure to novel objects, especially in ventral DG. We also found that novel objects produced higher c-fos levels than familiar objects. Interestingly, a small subset of neurons that did not express GluR2/3 also increased c-fos protein after novel object exposure. In contrast, GCs appeared relatively insensitive. The results support a growing appreciation of the role of the DG in novelty detection and novel object recognition, where hilar neurons and especially MCs are very sensitive.

An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy.

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

Potential implications of a monosynaptic pathway from mossy cells to adult-born granule cells of the dentate gyrus.

The dentate gyrus (DG) is important to many aspects of hippocampal function, but there are many aspects of the DG that are incompletely understood. One example is the role of mossy cells (MCs), a major DG cell type that is glutamatergic and innervates the primary output cells of the DG, the granule cells (GCs). MCs innervate the GCs as well as local circuit neurons that make GABAergic synapses on GCs, so the net effect of MCs on GCs - and therefore the output of the DG - is unclear. Here we first review fundamental information about MCs and the current hypotheses for their role in the normal DG and in diseases that involve the DG. Then we review previously published data which suggest that MCs are a source of input to a subset of GCs that are born in adulthood (adult-born GCs). In addition, we discuss the evidence that adult-born GCs may support the normal inhibitory 'gate' functions of the DG, where the GCs are a filter or gate for information from the entorhinal cortical input to area CA3. The implications are then discussed in the context of seizures and temporal lobe epilepsy (TLE). In TLE, it has been suggested that the DG inhibitory gate is weak or broken and MC loss leads to insufficient activation of inhibitory neurons, causing hyperexcitability. That idea was called the "dormant basket cell hypothesis." Recent data suggest that loss of normal adult-born GCs may also cause disinhibition, and seizure susceptibility. Therefore, we propose a reconsideration of the dormant basket cell hypothesis with an intervening adult-born GC between the MC and basket cell and call this hypothesis the "dormant immature granule cell hypothesis."