Editors' ChoiceEpilepsy

The vicious epigenetic cycle of neuronal activation

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Science Translational Medicine  22 Nov 2017:
Vol. 9, Issue 417, eaar2441
DOI: 10.1126/scitranslmed.aar2441


Seizure-induced increase in ΔFosB expression reduces calbindin-28k and might explain cognitive impairments in seizure disorders.

Recurrent seizures are often associated with cognitive impairments such as intellectual disability and autism, suggesting the existence of common underlying cellular and molecular mechanisms. Identifying these processes is critical to uncouple seizures and permanent cognitive disabilities. In a new study, You and colleagues addressed this issue and obtained novel insights.

Hippocampal samples collected from patients with Alzheimer’s disease (AD), who often present with seizures, show decreased hippocampal expression of a protein called calbindin-28k, major regulator of calcium signaling and hippocampal functions. Calbindin-28k expression is similarly reduced in hippocampus of patients with epilepsy, and its deletion leads to cognitive deficits in rodents. Starting from these observations, You and co-workers investigated the mechanism regulating calbindin-28k expression and its association with seizures and cognitive impairments.

Employing an AD mouse model, the group of researchers found that calbindin-28k expression is negatively correlated with the frequency of seizures, suggesting that its expression might be regulated by activity-dependent mechanisms. In agreement with this hypothesis, they found that calbindin-28k expression is epigenetically suppressed by the activity-dependent gene ΔFosB, whose expression increases with seizures. To understand the relevance of this observation, the authors quantified ΔFosB and calbindin-28k levels in hippocampal tissue obtained from patients diagnosed with temporal lobe epilepsy, mild cognitive impairment (MCI) or AD. The results show that ΔFosB and calbindin-28k expression levels were negatively correlated in patients diagnosed with epilepsy and MCI, and they correlated with the Folstein test score in AD patients, suggesting a functional link between ΔFosB/calbindin-28k and cognitive outcomes.

The authors furthermore reported that elevation of ΔFosB expression in the hippocampus caused cognitive deficits in experimental models. Genetically enhancing ΔFosB expression in mice impaired spatial memory; on the contrary, reducing ΔFosB expression in an AD mouse model partially rescued cognitive deficits.

In summary, the work of You and colleagues highlights an epigenetic mechanism linking epileptic seizures with cognition. Furthermore, although more research is required, this work points to a possible novel target for the treatment of cognitive deficits in seizure-related disorders. Finally, this study further points to the need of early subclinical seizure detection to prevent and ameliorate cognitive decay.

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