Figure 8.

Hypotheses for mossy cell vulnerability and function. (A) An illustration of the circuit components used in parts (B–D). Only some cell types in the DG are shown. Green cells and fibers represent glutamatergic cells and their axons; black cells and their red processes represent GABAergic neurons and their dendrites/axons. The triangular black cell represents the prototype of the GABAergic neuron, the basket cell. (B) The dormant basket cell hypothesis is illustrated schematically. Without mossy cell afferent input, basket cells do not have sufficient afferent input to inhibit granule cells. The result is disinhibition of granule cells. (C) The irritable mossy cell hypothesis is illustrated schematically. When mossy cells are activated, they directly excite granule cells. After traumatic brain injury, they discharge more. The net effect is more granule cell excitation. (D1) A representation of the lamellae of the hippocampus is shown. Brown = molecular layer. Gray = cell layers. (D2) A hypothesis that incorporates aspects of the dormant basket cell and irritable mossy cell hypotheses. (a) Mossy cell axons near their cell body, i.e., within the lamella of the mossy cell soma, innervate GABAergic neurons primarily, leading to inhibition of adjacent granule cells; (b) in distant lamella, the same mossy cells primarily excite granule cells. (D3) A schematic that illustrates a modification of the hypothesis of Lisman et al. (2005) to account for differences in circuitry across the septohippocampal axis, and GABAergic inhibition by the backprojecting axon collaterals of CA3 pyramidal cells. Following granule cell activation by the perforant path, CA3 activation by the mossy fibers will be followed by excitation of GABAergic neurons in the DG by CA3 backprojections [including the hilar dendrites of basket cells as shown; (Kneisler and Dingledine, 1995)]. The backprojection also innervates mossy cells which excite local GABAergic neurons. The result is silencing of recently active granule cells. In distal hippocampus, granule cells will be stimulated by the same mossy cells. CA3 backprojections in that location will then activate mossy cells which will project back to a lamella close to where activity began. This lamella is unlikely to be precisely the same as the original one because the extent that temporal mossy cells project to septal hippocampus is greater than the extent that septal mossy cells project to temporal levels. Note that the circuitry is simplified in the schematic for the purposes of illustration.