Summary: Following a seizure, deltaFosB remains in the hippocampus for an extensive period of time. Researchers believe this may contribute to memory loss and other cognitive deficits.
Source: Baylor College of Medicine.
Although it’s been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer’s disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, a team of researchers reveals a mechanism that can explain how even relatively infrequent seizures can lead to long-lasting cognitive deficits in animal models. A better understanding of this new mechanism may lead to future strategies to reduce cognitive deficits in Alzheimer’s disease and other conditions associated with seizures, such as epilepsy.
“It’s been hard to reconcile how infrequent seizures can lead to persistent changes in memory in patients with Alzheimer’s disease,” said corresponding author Dr. Jeannie Chin, assistant professor of neuroscience at Baylor College of Medicine. “To solve this puzzle, we worked with a mouse model of Alzheimer’s disease focusing on the genetic changes that seizures might trigger in the memory center of the brain, the hippocampus, that could lead to loss of memory or other cognitive deficits.”
The researchers measured the levels of a number of proteins involved in memory and learning and found that levels of the protein deltaFosB strikingly increase in the hippocampus of Alzheimer’s disease mice that had seizures. DeltaFosB already is well known for its association with other neurological conditions linked to persistent brain activity of specific brain regions, such as addiction. In this study, the researchers found that after a seizure, the deltaFosB protein remains in the hippocampus for an unusually long time; its half-life – the time it takes for the amount of protein to decrease by half – is eight days. Most proteins have a half-life that is between hours and a day or two.
“Interestingly, because deltaFosB is a transcription factor, meaning that its job is to regulate the expression of other proteins, these findings led us to predict that the increased deltaFosB levels might be responsible for suppressing the production of proteins that are necessary for learning and memory,” Chin said. “In fact, we found that when the levels of deltaFosB increase, those of other proteins, such as calbindin, decrease. Calbindin also has been known for a long time to be involved in Alzheimer’s disease and epilepsy, but its mechanism of regulation was not known. We then hypothesized that deltaFosB might be regulating the production of calbindin.”
Further investigations supported the researchers’ hypothesis. The scientists showed that deltaFosB can bind to the gene calbindin suppressing the expression of the protein. When they either prevented deltaFosB activity or experimentally increased calbindin expression in the mice, calbindin levels were restored and the mice improved their memory. And when researchers experimentally increased deltaFosB levels in normal mice, calbindin expression was suppressed and the animals’ memory deteriorated, demonstrating that deltaFosB and calbindin are key regulators of memory.
Connecting pieces of the puzzle
“Our findings have helped us answer the question of how even infrequent seizures can have such lasting detrimental effects on memory,” Chin said. “We found that seizures can increase the levels of deltaFosB in the hippocampus, which results in a decrease in the levels of calbindin, a regulator of memory processes. DeltaFosB has a relatively long half-life, therefore even when seizures are infrequent, deltaFosB remains in the hippocampus for weeks acting like a brake, reducing the production of calbindin and other proteins, and disrupting the consequent brain activity involved in memory. The regulation of gene expression far outlasts the actual seizure event that triggered it.”
The scientists found the same changes in deltaFosB and calbindin levels in the hippocampus of Alzheimer’s disease patients and in the temporal lobe of epilepsy patients. However, they underscore that it is too soon to know whether regulating deltaFosB or calbindin could improve or prevent memory problems or other cognitive deficits in people with Alzheimer’s disease. However, “now that we know that the levels of deltaFosB and calbindin are effective markers of brain activity in the hippocampus and memory function, we propose that these markers could potentially help assess clinical therapies for Alzheimer’s and other diseases with seizures,” Chin said.
Other contributors to this work include Jason C. You, Kavitha Muralidharan, Jin W. Park, Iraklis Petrof, Mark S. Pyfer, Brian F. Corbett, John J. LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A. Mohila, Daniel Yoshor, Robert A. Rissman, Eric J. Nestler and Helen E. Scharfman. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Thomas Jefferson University, New York University School of Medicine, Texas Children’s Hospital, University of California San Diego School of Medicine, VA San Diego Healthcare System and Icahn School of Medicine at Mount Sinai.
Funding: This work was supported by the Margaret Q. Landenberger Research Foundation, the Hassel Family Foundation, and the National Institutes of Health Grants NS085171, F30-AG048710, NYS OMH, 193 AG051848, BX003040, AG0051839 and AG005131.
Source: Graciela Gutierrez – Baylor College of Medicine
Publisher: Content organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com images is in the public domain.
Original Research: Abstract for “Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits” by Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman & Jeannie Chin in Nature Medicine. Published online October 16 2017 doi:10.1038/nm.4413
Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits
The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer’s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures8, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.
“Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits” by Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman & Jeannie Chin in Nature Medicine. Published online October 16 2017 doi:10.1038/nm.4413