Excitatory effects of dentate gyrus mossy cells and their ability to influence granule cell firing: an optogenetic study in adult mouse hippocampal slices

Abstract

ABSTRACTGlutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary cell type, granule cells (GCs), and GABAergic neurons which inhibit GCs. Prior studies suggest that the net effect of MCs is mainly to inhibit GCs, leading one to question why direct excitation of GCs is often missed. We hypothesized that MCs do have excitatory effects, but each GC is only excited weakly, at least under most experimental conditions. To address this hypothesis, MC axons were stimulated optogenetically in slices. A brief optogenetic stimulus to MC axons in the inner molecular layer (IML) led to a short-latency field EPSP (fEPSP) in the IML, suggesting there was a direct excitatory effect on GCs. Population spikes were negligible however, consistent with weak excitation. FEPSPs reflected AMPA/NMDA receptor-mediated EPSPs in GCs. EPSPs reached threshold after GC depolarization or facilitating NMDA receptors. GABAA and GABAB receptor-mediated IPSPs often followed EPSPs. At the network level, an optogenetic stimulus led to a brief, small facilitation of the PP-evoked population spike followed by a longer, greater inhibition. These data are consistent with rapid and selective GC firing by MCs (MC → GC) and disynaptic inhibition (MC → GABAergic neuron → GC). Notably, optogenetic excitation was evoked for both dorsal and ventral MCs, ipsilateral and contralateral MC axons, and two Cre lines. Together the results suggest a way to reconcile past studies and provide new insight into the balance of excitation and inhibition of GCs by MCs.SIGNIFICANCE STATEMENTMossy cells (MCs) of the dentate gyrus (DG) are glutamatergic and innervate granule cells (GCs). The net effect of MCs has been debated because MCs also innervate GABAergic neurons which inhibit GCs. The results shown here suggest that MCs excite numerous GCs, but excitation is weak at GC resting potentials, and requires specific conditions to trigger GC APs. The results are consistent with a GC network that is designed for selective activation.