Abstracts

Rationale: Febrile seizures (FS) are the most common form of seizures in children. Most FS are short and benign, but a subset of FS lasting longer than 30 minutes, termed febrile status epilepticus (FSE), may result in neurological injury. In the rat model for eFSE, cognitive outcomes vary by the degree of CA1 cell modulation by theta oscillations. Furthermore, eFSE leads to the attenuation of hippocampal pyramidal cell dendrites and the hyper-arborization of dentate granule cells. The morphological alterations in both subfields could alter throughput in the hippocampus and the integration of neocortical inputs that subserve spatial memory. However, throughput in the hippocampal circuit remains poorly understood. To this end we have developed a novel assay combining sensory stimulation and high-density hippocampal electrophysiology under urethane anesthesia.

Methods: Sprague-Dawley rat pups aged 10-11 days underwent eFSE induction for 60 minutes. Spatial cognition in the eFSE model is assessed using the active avoidance task on a rotating arena, a complex hippocampus-dependent spatial task. To measure circuit throughput in dorsal hippocampus, we used 64-channel probes to measure EEGs and single units across CA1 and dentate gyrus encompassing entorhinal synapses at SLM, OML and MML. Recordings were made under conditions of spontaneous activity, and then a “tail-pinch” was applied to noninvasively drive the sensory input to the hippocampal circuit. Following experiments, the hippocampus was rapidly dissected from the brain, and flash frozen for protein expression analysis via western blot.

Results: We confirmed previous findings that eFSE causes spatial learning and memory impairments in ~50% of rats. Using the laminar probes, simultaneous recordings across the CA1 somatodendritic axis allowed for the analysis of various input regions including the SLM, associated with L3 medial EC inputs, as well as oscillatory activity in the OML of the dentate gyrus. LFP recordings under urethane anesthesia during the tail pinch revealed that in the SLM and OML (associated with inputs from L2 of lateral EC) of eFSE rats, there was a significant decrease in peak and normalized theta power, suggesting that temporal organization by theta waves may be decreased by eFSE. Phase coherence between the CA1 cell layer and SLM was significantly reduced during the tail pinch, suggesting that inputs from L3 medial EC may not reach the cell body as effectively in eFSE as in controls. Using current source density analysis (figure 1), we have also shown that the dentate gyrus is hyperexcitable when EC is activated by the tail pinch, but inputs to CA1 are diminished.

Conclusions: Little is known about the mechanisms through which eFSE disrupts circuit throughput and affects behavior. Following early life eFSE, there are multiple hippocampal regions where aberrant signaling may contribute to memory deficits, including the CA1 and dentate gyrus. Work from our lab suggests that alterations to CA1 alone are not sufficient to impair spatial memory. We postulate that cognitive impairment after eFSE results from a multi-site alteration to normal synaptic signaling and connectivity.

Funding: Please list any funding that was received in support of this abstract.: NIH Grants NS108765 and NS108296.