Abstracts

Rationale: Febrile seizures are the most common childhood seizures, and when prolonged, febrile seizures causing febrile status epilepticus (FSE) can lead to temporal lobe epilepsy and cognitive impairment. The mechanisms by which FSE results in cognitive impairment remain unclear. Theta oscillations are critical for temporal coordination of the hippocampal network. Normal acetylcholine (ACH) signaling is necessary for learning and memory; disruption of ACH signaling alters CA1 oscillatory dynamics and impairs spatial memory in vivo. In the rodent model for experimental FSE (eFSE) hippocampal circuit function and cognition are impaired. Whether aberrant ACH signaling in hippocampus may contribute to disrupted circuit throughput observed following eFSE has not been shown. The goal of this study is to determine whether ACH synaptic activity in hippocampus is altered in vivo._x000D_
Methods: At postnatal day 10-11, eFSE was induced in male and female Sprague-Dawley rat pups via hyperthermia for 60 min. To study baseline physiology of hippocampal circuits, experiments were conducted under urethane anesthesia. Wideband EEG recordings were made with 64-channel laminar probes placed in dorsal hippocampus. A “tail-pinch” was applied to noninvasively drive the entorhinal-hippocampal circuit. This was followed by an IP injection of an acetylcholinesterase (ACHE) inhibitor to stimulate ACH-driven slow theta oscillations (2-5 Hz). Finally, a muscarinic or nicotinic ACH receptor antagonist was delivered via IP injection in separate experiments. The results of these pharmacological manipulations in vivo will indicate whether or not eFSE alters ACH circuits at the level of neural oscillations across hippocampus.

Results: Preliminary analyses of CTL and eFSE groups demonstrate significant changes to baseline tail pinch signal (TPS) peak and normalized power (2-5 Hz) and slow gamma frequency and normalized power (30-50 Hz). ACHE inhibition transitioned the circuit into an ACH-driven slow theta state independent of TPS, allowing for the comparison of ACH circuit activation across groups. ACH-driven slow theta peak and normalized power was comparable across all groups. Preliminary results further show that blockade of muscarinic ACH receptors revealed changes to circuit activity in eFSE during TPS and slow gamma bandwidths (both power and frequency), particularly during the tail pinch, throughout hippocampus compared with CTL. Ongoing analysis suggests that the eFSE-induced alterations to the spectral properties of theta and slow gamma oscillations in hippocampus may occur in a sex-specific manner.

Conclusions: These findings suggest that eFSE alters cholinergic signaling in hippocampus and address putative sex differences in baseline hippocampal circuit signaling and cholinergic modulation of hippocampal circuit function. These results provide new insight into the impact of eFSE on hippocampal circuits and may provide a mechanistic understanding for future therapeutic targets for cognitive impairment resulting from early life epilepsies.

Funding: This work was supported by a Postdoctoral Research Fellowship from the American Epilepsy Society to M.L.K. and NIH Grants NS108765 and NS108296 to J.M.B. and G.L.H.