Local and Long-Range Circuit Connections to Hilar Mossy Cells in the Dentate Gyrus

Abstract

Hilar mossy cells are the prominent glutamatergic cell type in the dentate hilus of the dentate gyrus (DG); they have been proposed to have critical roles in the DG network. To better understand how mossy cells contribute to DG function, we have applied new viral genetic and functional circuit mapping approaches to quantitatively map and compare local and long-range circuit connections of mossy cells and dentate granule cells in the mouse. The great majority of inputs to mossy cells consist of two parallel inputs from within the DG: an excitatory input pathway from dentate granule cells, and an inhibitory input pathway from local DG inhibitory neurons. Mossy cells also receive a moderate degree of excitatory and inhibitory CA3 input from proximal CA3 subfields. Long range inputs to mossy cells are numerically sparse, and they are only identified readily from the medial septum and the septofimbrial nucleus. In comparison, dentate granule cells receive most of their inputs from the entorhinal cortex. The granule cells receive significant synaptic connections from the hilus and the medial septum, and they also receive direct inputs from both distal and proximal CA3 subfields which has been under-described in the existing literature. Our slice-based physiological mapping studies further supported the identified circuit connections of mossy cells and granule cells. Together, our data suggest that hilar mossy cells are major local circuit integrators and they exert modulation of the activity of dentate granule cells as well as the CA3 region through “back-projection” pathways.

Significance Statement Hilar mossy cells are the neuron type of considerable interest in the dentate hilus. However, due to the technical difficulty of targeting mossy cells for in vivo circuit mapping, many aspects of local and long-range synaptic connections to these neurons remain uncharacterized. In this study, we used novel viral-genetic tracing and functional circuit mapping approaches to map and compare large-scale circuit connections to hilar mossy cells and dentate granule cells. We uncover previously unidentified circuits to hilar mossy cells and dentate granule cells. Our data support the proposal that hilar mossy cells function as major local circuit integrators of the dentate gyrus.