Abstracts

Rationale: Hippocampal sclerosis is a common finding in temporal lobe epilepsy (TLE), characterized by cell loss & gliosis in multiple hippocampal subfields and granule cell dispersion (GCD) in the dentate gyrus (DG). The supra-hippocampal kainic acid (KA) mouse model of TLE has extensive cell death & GCD and mossy fiber sprouting, capturing pathology seen in human with TLE. Furthermore, in between behavioral & electrographic seizures, interictal spikes (IS) can be observed in the hippocampus. We hypothesize that ISs are generated by dentate granule cells due to extensive pro-excitatory remodeling.

Methods: Wild-type mice were injected unilaterally with KA to induce status epilepticus (SE) which was subsequently terminated with diazepam. Spontaneous seizures became chronic after 4 weeks. Then, to investigate the circuit mechanisms behind ISs, we implanted high-density silicon probes to record freely moving mice during rest and during a hippocampal-dependent delayed spatial alternation task. Finally, we validate that dispersion and mossy fiber sprouting can be observed in our mouse model using prox-Cre mice to tag the dendrites and axons of granule cells using a viral vector.

Results: We find that interictal spikes occur at quiet rest and during task-online states. Interestingly, we also find correlates of dentate spikes (DS) in TLE mice, which have current source densities (CSD) that resemble normal DS, except spatially dispersed. We clustered the putative DS spikes into subtypes to locate current sinks in the middle and outer molecular layers (M/OMLs) which are driven by entorhinal cortex (EC) projections. This allowed us to infer the location of the inner ML (IML). We found that during ISs, large current sinks are observed in the putative IML and granule cell layers. Furthermore, -100 to +100 ms with respect to the peak of ISs, the CSDs have strong sinks the MML and OML respectively.

Conclusions: The observed patterns are consistent with the following conclusions: (1) IS are sustained by recurrent sprouted mossy fibers which synapse in the IML & granule cell layers, (2) EC excitatory input to the MML and OML potentially drives and is elicited by interictal activity. These findings open an exciting line of investigation into the mechanisms which may allow for the coexistence of “normal” DS and pathological IS in the same circuit.


Funding: This work was supported by NIH R01 (R01FG25962) to LAE.