Rabies tracing of birthdated dentate granule cells in rat temporal lobe epilepsy

To understand how monosynaptic inputs onto adult-born dentate granule cells (DGCs) are altered in experimental mesial temporal lobe epilepsy (mTLE) and whether their integration differs from early-born DGCs that are mature at the time of epileptogenesis.

A dual-virus tracing strategy combining retroviral birthdating with rabies virus-mediated putative retrograde trans-synaptic tracing was used to identify and compare presynaptic inputs onto adult-born and early-born DGCs in the rat pilocarpine model of mTLE.

Our results demonstrate that hilar ectopic DGCs preferentially synapse onto adult-born DGCs after pilocarpine-induced status epilepticus (SE), whereas normotopic DGCs synapse onto both adult-born and early-born DGCs. We also find that parvalbumin^- and somatostatin^- interneuron inputs are greatly diminished onto early-born DGCs after SE. However, somatostatin^- interneuron inputs onto adult-born DGCs are maintained, likely due to preferential sprouting. Intriguingly, CA3 pyramidal cell backprojections that specifically target adult-born DGCs arise in the epileptic brain, whereas axons of interneurons and pyramidal cells in CA1 appear to sprout across the hippocampal fissure to preferentially synapse onto early-born DGCs.

These data support the presence of substantial hippocampal circuit remodeling after an epileptogenic insult that generates prominent excitatory monosynaptic inputs, both local recurrent and widespread feedback loops, onto DGCs. Both adult-born and early-born DGCs are targets of new inputs from other DGCs as well as from CA3 and CA1 pyramidal cells after pilocarpine treatment, changes that likely contribute to epileptogenesis in experimental mTLE. Ann Neurol 2017;81:790-803.