Abstracts

Rationale: Seizures are a comorbidity of many neurological disorders; however, outcomes vary even among individuals with common disease etiology. Alzheimer’s disease (AD) is one example of a neurological disorder in which there is increased incidence of seizures, but not all patients develop seizures to the same extent. Notably, the occurrence of seizures predicts faster and more severe cognitive decline. It is unclear why some individuals appear resistant to the development of spontaneous recurrent seizures and cognitive decline. Understanding whether particular gene expression pathways confer resistance or susceptibility to seizures may help identify novel therapeutic strategies to treat or prevent seizures, which accompany a number of neurological disorders. Methods: We studied the human amyloid precursor protein (APP) transgenic mouse model of AD that exhibits robust spontaneous seizures, and found that individual APP mice differed vastly in seizure frequency even though they produce similar levels of amyloid-beta (Aβ). Spontaneous seizure activity correlated with memory deficits, such that APP mice with frequent seizures had poor memory, and APP mice that did not have seizures had normal memory. To study why some APP mice have frequent seizures and cognitive impairment while others do not, we stratified APP mice based on dentate gyrus expression of ΔFosB, a transcription factor whose expression we previously found correlates highly with seizure frequency. We performed RNA-sequencing on dentate gyrus from nontransgenic (NTG) control mice, APP mice with high ΔFosB levels (“APP-high”), and APP mice with control levels of ΔFosB similar to NTG mice (“APP-ctrl”). Results: APP-high mice differed the most in gene expression patterns compared with NTG mice and APP-ctrl mice. Gene clustering analyses revealed that the expression differences between APP-high mice and NTG or APP-ctrl mice involved many ion channels and excitability-related genes. Surprisingly, despite having similarly high levels of APP/Aβ, APP-ctrl mice had gene expression profiles largely different from that of APP-high mice, but very similar to that of NTG mice. Notably, a small set of genes were differentially expressed in APP-ctrl mice compared with either NTG or APP-high mice. Conclusions: These results indicate that APP-high mice are different from both NTG mice and APP-ctrl mice, in terms of seizures occurrence, memory function, and gene expression patterns. Of note, a small set of genes differentiates APP-ctrl mice from NTG or APP-high mice, suggesting they may play a role in conferring resistance to the effects of Aβ and/or seizures. Understanding how these varying patterns of gene expression arise may provide insight into mechanisms that underlie differential susceptibility to seizures and associated cognitive deficits in neurological disorders accompanied by seizures. Funding: This work was funded by NIH NS086965 and NS085171 (JC).