Non-synaptic interictal epileptiform discharges propagating from CA3 to CA1 induce synaptic depression in the hippocampus

Epilepsia Open. 2025 Jul 9. doi: 10.1002/epi4.70098. Online ahead of print.

ABSTRACT

OBJECTIVE: Patients with epilepsy contend with memory impairment associated with the prevalence of interictal epileptiform discharges (IEDs). IEDs can propagate without synaptic transmission in both in vivo and in vitro rodent hippocampi. We focused our investigation on the effects of these non-synaptically propagating IEDs on synaptic plasticity. Specifically, we tested the hypothesis that such IEDs generate long-term depression.

METHODS: IEDs were induced in mouse longitudinal hippocampal slices (i.e., cut along the septotemporal axis of the hippocampus) using 4-aminopyridine (4-AP). Changes in amplitudes and slopes of the population excitatory evoked postsynaptic potentials (pEPSPs) were measured from the CA1 apical dendrite following stimulation at the Schaffer collaterals. Direct current stimulation (DCS) was applied to study the interaction between applied electric fields and IED-induced synaptic plasticity.

RESULTS: Following long-term potentiation, 4-AP-induced IEDs were observed to propagate along the slice and in the slice generated significant depression as evidenced by a significant decrease in pEPSP slope. Analysis revealed an inverse relationship between IED frequency and synaptic depression magnitude, with lower-frequency IEDs producing more pronounced synaptic downregulation. In addition, anodal DCS effectively canceled the LTD-like effect induced by 4-AP IEDs, restoring synaptic strength. In contrast, cathodal DCS failed to modify or reverse the 4-AP-induced synaptic depression.

SIGNIFICANCE: This study provides insights into how non-synaptic IEDs contribute to synaptic plasticity alterations, offering a potential mechanism for memory impairment in epilepsy. The results highlight the therapeutic potential of anodal DCS for mitigating IED-related cognitive deficits.

PLAIN LANGUAGE SUMMARY: People with epilepsy often have memory problems, which may be linked to abnormal brain activity called interictal epileptiform discharges (IEDs). In this study, we found that these discharges can weaken connections between brain cells, possibly explaining some memory issues. We also found that applying a gentle electrical current to the brain (called anodal direct current stimulation) could prevent this weakening. These results suggest a possible new approach to reduce memory problems in epilepsy.

PMID:40632649 | DOI:10.1002/epi4.70098