Enduring Memory Impairments Provoked by Developmental Febrile Seizures Are Mediated by Functional and Structural Effects of Neuronal Restrictive Silencing Factor.

In a subset of children experiencing prolonged febrile seizures (FSs), the most common type of childhood seizures, cognitive outcomes are compromised. However, the underlying mechanisms are unknown. Here we identified significant, enduring spatial memory problems in male rats following experimental prolonged FS (febrile status epilepticus; eFSE). Remarkably, these deficits were abolished by transient, post hoc interference with the chromatin binding of the transcriptional repressor neuron restrictive silencing factor (NRSF or REST). This transcriptional regulator is known to contribute to neuronal differentiation during development and to programmed gene expression in mature neurons. The mechanisms of the eFSE-provoked memory problems involved complex disruption of memory-related hippocampal oscillations recorded from CA1, likely resulting in part from impairments of dendritic filtering of cortical inputs as well as abnormal synaptic function. Accordingly, eFSE provoked region-specific dendritic loss in the hippocampus, and aberrant generation of excitatory synapses in dentate gyrus granule cells. Blocking NRSF transiently after eFSE prevented granule cell dysmaturation, restored a functional balance of γ-band network oscillations, and allowed treated eFSE rats to encode and retrieve spatial memories. Together, these studies provide novel insights into developing networks that underlie memory, the mechanisms by which early-life seizures influence them, and the means to abrogate the ensuing cognitive problems.SIGNIFICANCE STATEMENT Whereas seizures have been the central focus of epilepsy research, they are commonly accompanied by cognitive problems, including memory impairments that contribute to poor quality of life. These deficits often arise before the onset of spontaneous seizures, or independent from them, yet the mechanisms involved are unclear. Here, using a rodent model of common developmental seizures that provoke epilepsy in a subset of individuals, we identify serious consequent memory problems. We uncover molecular, cellular, and circuit-level mechanisms that underlie these deficits and successfully abolish them by targeted therapeutic interventions. These findings may be important for understanding and preventing cognitive problems in individuals suffering long febrile seizures.

Spatial cognition following early-life seizures in rats: Performance deficits are dependent on task demands.

Cognitive impairment is a common comorbidity in childhood epilepsy. Studies in rodents have demonstrated that frequent seizures during the first weeks of life result in impaired spatial cognition when the rats are tested as juvenile or adults. To determine if spatial cognitive deficits following early-life seizures are task-specific or similar across spatial tasks, we compared the effects of early-life seizures in two spatial assays: 1) the Morris water maze, a hippocampal-dependent task of spatial cognition and 2) the active avoidance task, a task that associates an aversive shock stimulus with a static spatial location that requires intact hippocampal-amygdala networks. Rats with early-life seizures tested as adults did not differ from control rats in the water maze. However, while animals with early-life seizures showed some evidence of learning the active avoidance task, they received significantly more shocks in later training trials, particularly during the second training day, than controls. One possibility for the performance differences between the tasks is that the active avoidance task requires multiple brain regions and that interregional communication could be affected by alterations in white matter integrity. However, there were no measurable group differences with regard to levels of myelination. The study suggests that elucidation of mild cognitive deficits seen following early-life seizures may be dependent on task features of active avoidance.