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. Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits. Nat Med. 2017 Nov;23(11):1377-1383. Epub 2017 Oct 16 PubMed.
Recommends
Please login to recommend the paper.
Comments
Baylor College of Medicine
Chronic hippocampal seizures impair cognition, an all-too-common biological comorbidity of temporal lobe epilepsy. What can be done? In the face of irreversible hippocampal cell loss followed by extensive structural rearrangements due to axonal sprouting, dendritic spine loss, and neosynaptogenesis, the prospect of restoring native memory networks has long seemed remote. At the molecular remodeling level, the relative plasticity of heteromeric GABAergic receptor subunit stoichiometry, altered transmembrane chloride gradients, and reduced sodium ion channel current density seem to offer a chance, however slim, of selectively reversing impaired synaptic strength, but these targets have not yet led to effective treatments.
Now the search for reversible pathophysiology has taken an important new turn. From within the riptides of transcriptional dysregulation long known to occur in dentate granule cells following seizures, Chin and collaborators have isolated a critical pathway centering on the newfound ability of the transcription factor ΔFosB to modulate intracellular calcium buffering by suppressing calbindin-D28, an epigenetic switch that may offer a tractable target for restoring membrane excitability by regulating channel kinetics and other steps in neurotransmitter release.
Ironically, as one of the members of the immediate early gene family long used as a nuclear biomarker for tracing neuronal hyperactivity, ΔFosB has been hiding in plain sight. Chin showed in a convulsant model of seizures, and in the genetic AD mouse model where behaviorally silent hippocampal epilepsy was first observed, that when seizures stimulate excess calcium entry into granule cells, ΔFosB and ΔFosB alone is sufficient to suppress Calb1 transcription by interfering with promotor-level transcriptional control, resulting in neuronal hyperexcitability. Clever use of a dominant negative interaction with JunD protein to prevent chromatin modification at the promoter region preserved calbindin levels and prevented induced spatial memory deficits.
This is a welcome discovery revealing an epigenetic target for protection against seizure-induced malfunction of hippocampal circuitry, even in the face of other structural cellular pathology. Not all patterns of epilepsy trigger immediate early gene expression, even in the presence of axonal sprouting, and leave calbindin levels undisturbed, which may account for relative sparing of cognition (Nahm et al., 1998), however, a single strong hippocampal seizure may lead to transient amnesia that might reflect a brief suppression of neuronal calbindin levels. In addition, as the authors suggest, this mechanism could well extend to other clinical etiologies of learning and memory impairment that are below the threshold for classically measurable hypersynchronous discharges.
References:
Nahm WK, Noebels JL. Nonobligate role of early or sustained expression of immediate-early gene proteins c-fos, c-jun, and Zif/268 in hippocampal mossy fiber sprouting. J Neurosci. 1998 Nov 15;18(22):9245-55. PubMed.
View all comments by Jeffrey L. NoebelsMake a Comment
To make a comment you must login or register.