EPIGENETIC REGULATION OF HIPPOCAMPAL FUNCTION AND COGNITION
Cognitive deficits are a comorbidity of many neurological disorders that are accompanied by recurrent seizures, including AD and epilepsy. However, the mechanisms by which seizures induce cognitive deficits that persist even in seizure-free periods are not well understood. We found that seizures increase hippocampal expression of ∆FosB, an immediate-early gene with an unusually long half-life that allows it to accumulate for weeks after even a single seizure. ∆FosB can impair hippocampal memory by binding to and inducing epigenetic suppression of target genes; two that we have characterized in mouse models of AD and epilepsy are c-Fos and calbindin, which play critical roles in regulating cognitive function. This work highlights a novel mechanism that links seizures to long-lasting changes in gene expression that far outlast the seizure activity, and can help explain why even infrequent seizures can be associated with persistent deficits in cognition. Given that ∆FosB may have thousands of target genes, we conducted a ChIP-sequencing study to identify the repertoire of genes differentially regulated in mice with seizures. Our findings reveal a functional diversification of targets bound by ∆FosB in AD and epilepsy mice compared to controls, indicating that ∆FosB regulates different modes of gene expression under normal conditions and conditions of chronic hyperexcitation. Ongoing research focuses on identifying functional domains that are controlled by ∆FosB-mediated epigenetic regulation of gene expression, to understand the extent and mechanisms by which seizures alter normal brain function.
Related publications:
Stephens G, Park J, Eagle A, You J, Silva-Perez M, Fu C-H, Choi S, St. Romain C, Sugimoto C, Buffington S, Zheng Y, Costa-Mattioli M, Liu Y, Robison AJ, Chin J (2024) Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice. Progress in Neurobiology (in press).
Clasadonte J*, Deprez T*, Stephens G*, Mairet-Coello G, Cortin P-Y, Boutier M, Frey A, Chin J, Rajman M (2023) ΔFosB is part of a homeostatic mechanism that protects the epileptic brain from further deterioration. Frontiers in Molecular Neuroscience 16:1324922.
Fu C-H, You JC, Mohila C, Rissman RA, Yoshor D, Viaene A, Chin J (2023) ∆FosB expression is associated with cognitive impairment in a subgroup of patients with childhood epilepsies. Frontiers in Neurology 14:1331194.
Stephens GS, Fu CH, St. Romain CP, Zheng Y, Botterill JJ, Scharfman HE, Liu Y, Chin J (2020) Genes bound by ∆FosB in different conditions with recurrent seizures regulate similar neuronal functions. Frontiers in Neuroscience 14:472. [PMID: 32536852].
You JC*, Stephens GS*, Fu CH, Zhang XH, Liu Y, Chin J (2018). Genome-wide profiling reveals functional diversification of ∆FosB gene targets in the hippocampus of an Alzheimer’s disease mouse model. PLoS One 13(2):e0192508. [PMID 29408867]
You JC, Muralidharan K, Park JW, Petrof I, Pyfer MS, Corbett BF, LaFrancois JJ, Zheng Y, Zhang X, Mohila CA, Yoshor D, Rissman RA, Nestler EJ, Scharfman HE, Chin J(2017) Epigenetic suppression of hippocampal calbindin-D28K by ∆FosB drives seizure-related cognitive deficits. Nature Medicine 23(11):1377-1383. [PMID: 17051202]
Corbett BF, You JC, Zhang X, Pyfer MS, Tosi U, Iascone DM, Peterof I, Hazra A, Fu C-H, Stephens GS, Ashok AA, Aschmies A, Zhao L, Nestler EJ, Chin J (2017) ∆FosB regulates gene expression and cognitive dysfunction in a mouse model of Alzheimer’s disease. Cell Reports 20(2):344-355. [PMID 28700937]
Chin J and Scharfman HE (2013) Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy Behav 26(3):343-351. [PMID: 23321057]
TRN (DYS)FUNCTION IN SLEEP DEFICITS AND ABETA ACCUMULATION IN ALZHEIMER’S DISEASE
Alzheimer’s disease is characterized by severe loss of memory, and is also accompanied by a number of other debilitating symptoms including sleep disturbances, attention deficits, and subclinical epileptiform activity. How such diverse symptoms arise and affect multiple cognitive and behavioral domains is unknown, making it difficult to develop therapeutic strategies that can treat all of these aspects in AD. We found that AD mouse models exhibit decreased activity in the thalamic reticular nucleus (TRN), which controls sleep maintenance, slow wave sleep, attention, and other cognitive functions, indicating the TRN may be a master regulator of multiple domains that are affected in AD. Notably, slow wave sleep is the phase of sleep during which metabolites and solutes such as Aβ are cleared from the brain, suggesting that the decreased activity of TRN in AD mice may also contribute to plaque deposition. We are now testing whether DREADD-mediated restoration of activity in the TRN can normalize sleep, reduce pathology, and improve memory function in Alzheimer’s disease.
Related publications:
Jagirdar R, Fu CH, Park J, Corbett B, Seibt FM, Beierlein M, Chin J (2021) Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Abeta accumulation in mice. Science Translational Medicine 13:618. DOI: 10.1126/scitranslmed.abh4284
O'Malley JJ, Seibt F, Chin J, Beierlein M (2020) TRPM4 conductances in thalamic reticular nucleus neurons generate persistent firing during slow oscillations. Journal of Neuroscience 40(25):4813-4823. [PMID: 32414784]
Jagirdar R, Chin J (2019) Corticothalamic network dysfunction and Alzheimer’s disease. Brain Research 1702:38-45. [PMID 28919464] Epub 2017
Hazra A*, Corbett BF*, You JC, Aschmies SA, Zhao L, Li K, Lepore A, Marsh ED, Chin J (2016) Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer’s disease Neurobiol Aging 44:96-107. [PMID 27318137]
ACCELERATED DEPLETION OF THE HIPPOCAMPAL NEURAL STEM CELL POOL IN NEUROLOGICAL DISEASE
Adult hippocampal neurogenesis has received much attention for understanding human cognition and mood, and the potential of developing therapeutic strategies for disorders such as epilepsy, AD, and depression. The seizures that occur in epilepsy and in AD may disrupt the dynamics of neurogenesis; studies in rodent models have demonstrated that seizures acutely trigger neural stem cell (NSC) division and neurogenesis, but chronic recurrent seizures are associated with decreased neurogenesis. We recently published a network mechanism that underlies this phenomenon in AD mice, which also occurs in an epilepsy model. We found recurrent seizures accelerate the use and depletion of a finite pool of hippocampal neural stem cells. This mechanism accounts for the early increases and later reductions in adult-born neurons, and leads to deficits in spatial discrimination, a function that relies on adult-born neurons. We characterized spatial discrimination in APP mice at different stages of disease progression: Early in disease, prior to the occurrence of robust seizures, there is no loss of adult-born neurons in APP mice, and spatial discrimination is indistinguishable between APP mice and NTG control mice. But, when levels of adult-born DG neurons in APP mice fall below that in NTG mice, spatial discrimination becomes (and stays) impaired in APP mice. Spatial discrimination ability appears to be tightly linked to even subtle changes in adult-born neurons, whereas depressive-like behaviors are less so. Such assessment of neurogenesis-dependent behaviors throughout disease progression also serves as a basis for designing and interpreting therapeutic strategies. We are currently investigating the multi-modal mechanisms by which hippocampal NSCs “sense'“ the level of activity in the hippocampus, and how these processes are hijacked by seizures to override the typically tight control of hippocampal neurogenesis.
Related publications:
You JC*, Muralidharan K*, Fu CH, Park J, Tosi U, Zhang X, Chin J (2020) Distinct patterns of dentate gyrus cell activation distinguish physiologic from aberrant stimuli. PLoS One 15(5): e0232241. [PMID: 32407421]
Fu CH*, Iascone DM*, Petrof I, Hazra A, Zhang X, Pyfer MS, Tosi U, Corbett BF, Cai J, Lee J, Park J, Iacovitti L, Scharfman HE, Enikolopov G, Chin J (2019) Early seizure activity accelerates depletion of hippocampal neural stem cells and impairs spatial discrimination in an Alzheimer's disease model. Cell Reports 27(13):3741-3751. [PMID: 31242408]
Iascone DM, Padidam S, Pyfer MS, Zhao L, Zhang X, and Chin J (2013) Impairments in neurogenesis are not tightly linked to depressive behavior in a transgenic mouse model of Alzheimer’s disease. PLoS ONE 8(11):e79651. [PMID 24244537]
Chin J and Scharfman HE (2013) Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy Behav 26(3):343-351. [PMID: 23321057]
Other research interests: modulation of behavioral state in neurological disease, neuropsychiatric symptoms of AD and epilepsy, susceptibility and resistance factors that influence disease risk
our work is funded by past and present support from:
HASSEL FAMILY FOUNDATION * MARGARET Q. LANDENBERGER RESEARCH FOUNDATION * INSTITUTE FOR CLINICAL SCIENCE AND ART
UNLOCKING THE MYSTERIES OF THE BRAIN
