Spatial learning impairments and discoordination of entorhinal-hippocampal circuit coding following prolonged febrile seizures.

How the development and function of neural circuits governing learning and memory are affected by insults in early life remains poorly understood. The goal of this study was to identify putative changes in cortico-hippocampal signaling mechanisms that could lead to learning and memory deficits in a clinically relevant developmental pathophysiological rodent model, Febrile status epilepticus (FSE). FSE in both pediatric cases and the experimental animal model, is associated with enduring physiological alterations of the hippocampal circuit and cognitive impairment. Here, we deconstruct hippocampal circuit throughput by inducing slow theta oscillations in rats under urethane anesthesia and isolating the dendritic compartments of CA1 and dentate gyrus subfields, their reception of medial and lateral entorhinal cortex inputs, and the efficacy of signal propagation to each somatic cell layer. We identify FSE-induced theta-gamma decoupling at cortical synaptic input pathways and altered signal phase coherence along the CA1 and dentate gyrus somatodendritic axes. Moreover, increased DG synaptic activity levels are predictive of poor cognitive outcomes. We propose that these alterations in cortico-hippocampal coordination interfere with the ability of hippocampal dendrites to receive, decode and propagate neocortical inputs. If this frequency-specific syntax is necessary for cortico-hippocampal coordination and spatial learning and memory, its loss could be a mechanism for FSE cognitive comorbidities.

Recurrent febrile seizures alter intrahippocampal temporal coordination but do not cause spatial learning impairments.

OBJECTIVE: Febrile seizures (FSs) are the most common form of seizures in children. Single short FSs are benign, but FSs lasting longer than 30 min, termed febrile status epilepticus, may result in neurological sequelae. However, there is little information about an intermediary condition, brief recurrent FSs (RFSs). The goal of this study was to determine the role of RFSs on spatial learning and memory and the properties of spontaneous hippocampal signals. METHODS: A hippocampus-dependent active avoidance task was used to assess spatial learning and memory in adult rats that underwent experimental RFSs (eRFSs) in early life compared with their littermate controls. Following completion of the task, we utilized high-density laminar probes to measure spontaneous hippocampal CA1 circuit activity under urethane anesthesia, which allowed for the simultaneous recording of input regions in CA1 associated with both CA3 and entorhinal cortex. RESULTS: RFSs did not result in deficits in the active avoidance spatial test, a hippocampus-dependent test of spatial learning and memory. However, in vivo high-density laminar electrode recordings from eRFS rats had significantly altered power and frequency expression of theta and gamma bandwidths as well as signaling efficacy along the CA1 somatodendritic axis. Thus, although eRFS modified CA1 neuronal input/output dynamics, these alterations were not sufficient to impair active avoidance spatial behavior. SIGNIFICANCE: These findings indicate that although eRFSs do not result in spatial cognitive deficits in the active avoidance task, recurrent seizures do alter the brain and result in longstanding changes in the temporal organization of the hippocampus.