Mechanisms Underlying Hyperexcitability: Combining Mossy Fiber Sprouting and Mossy Cell Loss in Neural Network Model of the Dentate Gyrus

Abstract

Background/Objectives: A concussive head injury increases the likelihood of temporal lobe epilepsy through mechanisms that are not entirely understood. This study aimed to investigate how two key histopathological features shared by both TLE (temporal lobe epilepsy) and head injury-mossy fiber sprouting and hilar excitatory cell loss-contribute to the modulation of dentate gyrus excitability. Methods: A computational approach was used to explore the impact of specific levels of mossy fiber sprouting and mossy cell loss, while avoiding the confounding effects of concurrent changes. The dentate gyrus model consists of 500 granule cells, 15 mossy cells, 6 basket cells and 6 hilar perforant path-associated cells. Results: My simulations demonstrate a correlation between the degree of mossy fiber sprouting and the number of spikes in dentate gyrus granule cells (correlations coefficient R = 0.95, p < 0.0001) and other cells (correlations coefficient R = 0.99, p < 0.0001). The mean values (standard deviation, SD) and 95% CI for granule cell activity in the control group and percentage 10-50% of mossy fiber sprouting groups are 376.4 (16.7) (95% CI, 374.9-377.8) vs. 463.5 (24.3) (95% CI, 461.4-465.6) vs. 514.8 (32.5) (95% CI, 511.9-517.6) vs. 555.0 (40.4) (95% CI, 551.5-558.6) vs. 633.4 (51.8) (95% CI, 628.8-637.9) vs. 701.7 (66.2) (95% CI, 695.9-707.5). The increase in mossy fiber sprouting was significantly statistically associated with an increase in granule cell activity (p < 0.01). The removal of mossy cells led to a reduction in excitability within the model network (for granule cells, correlations coefficient R = -0.40, p < 0.0001). Conclusions: These results are generally consistent with experimental observations, which indicate a high degree of mossy fiber sprouting in animals with a higher frequency of seizures. Whereas unlike the strong hyperexcitability effects induced by mossy fiber sprouting, the removal of mossy cells led to reduced granule cell responses to perforant path activation.

Keywords: dentate gyrus; epilepsy; mossy cell loss; mossy fiber sprouting; networks model.

Figure 1

Anatomy of Dentate Circuits. (A) Schematic of hippocampal structures including the DG, CA3, and CA1. In a healthy brain, mossy fibers are the axons that arise from glutamatergic dentate granule cells found within the granule cell layer of the dentate gyrus. Healthy mossy fibers provide input to CA3 pyramidal cells. DG granule cells received excitatory inputs from the entorhinal cortex 2 (EC2). (B) A representation of the simulated microcircuit model of the DG network, granule cells G, mossy cells M, basket cells B, hilar perforant path-associated cells H, and medial-septum-diagonal band (MS). (C) In the epileptic hippocampus, the loss of mossy fiber targets in the hilus leads granule cell axons to sprout and densely innervate the inner molecular layer of the dentate gyrus, a process known as mossy fiber sprouting. (D) In the case of mossy cell loss, chosen mossy cells were effectively “killed” by removing all synapses linked to and from these “dead” cells (dashed line).

Figure 2

The cell activity (spikes) in the control group and mossy fiber sprouting groups. (A) Granule cell activity. (B) Mossy cell activity. (C) Basket cell activity. (D) Hilar perforant path-associated cell activity.

Figure 3

Interspike interval in the control group and mossy fiber sprouting groups. (A) Granule cell activity. (B) Mossy cell activity. (C) Basket cell activity. (D) Hilar perforant path-associated cell activity.

Figure 4

Granule cell membrane voltage traces (PSP—postsynaptic potential) during the first second of the simulation.

Figure 5

Mossy fiber sprouting increases excitability in the dentate network. (A–F) Spike raster plots illustrating granule cell activity in the networks in response to perforant path input stimulation ((A)—control, (B–F) mossy fiber sprouting groups 10–50%). (G–L) Spike raster plots illustrating mossy, basket and hilar perforant path-associated cells activity in the networks in response to perforant path input stimulation ((G)—control, (H–L) mossy fiber sprouting groups 10–50%) (red—granule cell, orange—mossy cell, blue—basket cell, gray—hilar perforant path-associated cell).

Figure 6

The cell activity (spikes) in the control group and mossy fiber sprouting groups and 50% mossy cell loss. (A) Granule cell activity. (B) Mossy cell activity. (C) Basket cell activity. (D) Hilar perforant path-associated cell activity.

Figure 7

Interspike interval in the control group and mossy fiber sprouting groups and 50% mossy cell loss. (A) Granule cell activity. (B) Mossy cell activity. (C) Basket cell activity. (D) Hilar perforant path-associated cell activity.

Figure 8

Impact of mossy cell loss and sprouting on dentate network excitability. (A–E) Spike raster plots illustrating granule cell activity in the networks in response to perforant path input stimulation ((A–E) mossy cell loss and sprouting groups 10–50%). (F–J) Spike raster plots illustrating mossy, basket and hilar perforant path-associated cells activity in the networks in re-sponse to perforant path input stimulation ((F–J) mossy cell loss and sprouting groups 10–50%) (red—granule cell, orange—mossy cell, blue—basket cell, gray—hilar perforant path-associated cell).