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Seizures cause memory and cognitive loss by blocking expression of a neuronal calcium sensor
A collaborative study led by Dr. Jeannie Chin, assistant professor at Baylor College of Medicine and Texas Children's Hospital has identified a novel mechanism by which recurrent seizures induce suppression of calbindin-D28k, a crucial calcium sensor in neurons, leading to cognitive deficits. The study published in Nature Medicine has broad implications for seizure-related disorders like epilepsy, autism, schizophrenia, dementia and Alzheimer’s disease (AD) that impair memory and cognition.
In this study, researchers have discovered a new mechanism by which seizures increase the levels of ∆FosB, a transcriptional regulator, which then switches off the expression of calbindin in the hippocampus of patients with epilepsy, mild cognitive impairment, or AD, as well as in animal models of these disorders.
Seizures accompany many neurological disorders including epilepsy, dementia, AD, autism and are thought to contribute to memory loss and cognitive decline.
Calbindin-D28k protein controls neuronal calcium signaling which is crucial for optimal memory processing and cognitive function. Previous studies in patients and mouse models of Alzheimer’s disease and epilepsy had shown that the severity of cognitive deficits correlates directly to how low the levels of calbindin-D28k are in the hippocampus, a region of the brain crucial for memory formation. However, the mechanism of how calbindin-D28k level in the hippocampus was regulated was not known.
In this study, scientists noticed that reduction in hippocampal calbindin correlated inversely to the frequency of seizures in mouse models of AD and epilepsy and lasted long after the seizures had occurred.
To understand how brain activity like a seizure could have such a profound and long-lasting effect on the expression of calbindin, researchers turned to DFosB, a long-lived master regulator that has been reported to switch on/off the expression of many genes. Calbindin was a prime candidate for such regulation by ∆FosB, although it had never been shown before.
Interestingly, ∆FosB levels were elevated in the hippocampus of AD and epilepsy mice. Further analysis showed that ∆FosB alters the tightly coiled 3-D conformation of the chromatin region around calbindin gene. The modified chromatin was inaccessible to other regulatory proteins, chronically suppressing the expression of calbindin. Furthermore, experimentally increasing calbindin levels or blocking of the actions of ∆FosB improved spatial memory in the mouse models of AD, demonstrating a direct causal effect.
The researchers then tested if seizure-induced cognitive decline in AD and epilepsy patients occurs via similar mechanisms. They were excited to note that not only was ∆FosB expression elevated but that it also correlated with reduced calbindin expression in the hippocampus of patients, as predicted from their studies in animal models. Furthermore, levels of hippocampal calbindin and ∆FosB in patients with mild cognitive impairment and epilepsy were clearly indicative of their performance in cognitive tests.
By identifying key molecular players and mechanisms that regulate seizure-induced cognitive decline, this study provides hope that new therapies can now begin to be developed, which will immensely help patients suffering from many neurological disorders.