Abstracts

Rationale:
Temporal lobe epilepsy (TLE) is characterized by spontaneous and recurring seizures as well as pervasive memory impairments that significantly impact patient quality of life. To develop new treatments for these cognitive deficits, it is imperative to understand how epilepsy alters temporal lobe circuitry that is a key node in memory processing. In previous work, our lab and others have established CA1 of dorsal hippocampus (dCA1) as a site of poor spatial processing in epileptic mice. However, it remains unclear if upstream medial entorhinal cortex (MEC) inputs to dCA1 are impaired, and how they contribute to downstream changes in hippocampus. Here, we tested the hypothesis that MEC has disrupted spatial coding in epileptic mice by recording neural activity in distinct hippocampal inputs from layer 3 (MECIII) pyramidal neurons and layer 2 (MECII) stellate cells in control and epileptic mice.

Methods:
We performed in vivo calcium imaging in MECII stellate cells and MECIII excitatory neurons in control and pilocarpine-treated epileptic mice as they ran on a linear track, explored an open field, and performed a novel object location memory task. We employed novel viral vector constructs for layer specific expression of a calcium indicator, GCaMP8m, in MEC that isolated MECII stellate cells and MECIII neurons. To examine how MEC circuits were disrupted across the development of epilepsy, we recorded animals both three and eight weeks after pilocarpine-induced status epilepticus, which coincides with progressive memory and spatial coding deficits in this model.

Results:
We found that MECIII pyramidal neurons, which directly input to dCA1, have altered spatial coding with a similar time course to memory and dCA1 deficits, implicating this circuit in mediating progressive memory impairments in epilepsy. Additional preliminary evidence suggests that dentate gyrus-projecting MECII stellate cells do not have progressive changes in spatial coding in epileptic mice that could account for the onset of CA1 coding and memory deficits. Together, these results indicate that progressive degradation of MECIII spatial representations likely contributes to memory impairments in epilepsy and may be an ideal circuit to target with new interventions.

Conclusions:
These results suggest that dCA1 spatial coding deficits may be due in part to altered inputs and implicates upstream MECIII an important site of functional pathology in TLE. This work is the first to characterize MEC spatial coding deficits in epilepsy and indicates that altered circuits driving memory impairments extend beyond the hippocampus. These findings suggest that MECIII may be an ideal target for future therapeutics to treat the cognitive deficits associated with TLE.

Funding: