Adaptive Mossy Cell Circuit Plasticity after Status Epilepticus.

Area of Science:

• Neuroscience
• Epilepsy Research
• Hippocampal Circuitry

Background:

• Hilar mossy cells are crucial for hippocampal network function, mediating both excitation and inhibition of dentate granule cells (DGCs).
• Epilepsy is characterized by significant mossy cell loss and altered hippocampal circuit function, contributing to hyperexcitability.

Purpose of the Study:

• To investigate the functional contribution of surviving mossy cells to network activity in the reorganized dentate gyrus following pilocarpine-induced status epilepticus (SE).
• To elucidate adaptive plasticity in mossy cell outputs and their impact on the excitation/inhibition balance in the epileptic hippocampus.

Main Methods:

• Utilized optogenetics to stimulate mossy cells in acute hippocampal slices from control and pilocarpine-treated mice.
• Examined monosynaptic excitatory and di-synaptic inhibitory currents in DGCs and excitation of parvalbumin-positive (PV+) basket cells.
• Employed transgenic mice, translational mouse modeling, and viral vectors for selective functional circuit analysis.

Main Results:

• Mossy cell density and their excitatory drive onto DGCs were reduced post-SE.
• Mossy cell-driven excitation of PV+ basket cells, key mediators of feedforward inhibition, was preserved.
• The overall effect of surviving mossy cells shifted towards increased net inhibition of DGCs due to maintained feedforward inhibition.

Conclusions:

• Mossy cell outputs undergo adaptive reorganization following seizures, enhancing their inhibitory influence on the hippocampal network.
• The preserved mossy cell-driven excitation of PV+ interneurons suggests a homeostatic mechanism to counteract hyperexcitability.
• These findings highlight potential therapeutic strategies targeting the reorganized mossy cell-interneuron microcircuit in epilepsy.