Epigenetic modulation of seizure-induced neurogenesis and cognitive decline.
The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task. We propose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.
Jessberger
Sebastian
S
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nakashima
Kinichi
K
Clemenson
Gregory D
GD
Mejia
Eunice
E
Mathews
Emily
E
Ure
Kerstin
K
Ogawa
Shiori
S
Sinton
Christopher M
CM
Gage
Fred H
FH
Hsieh
Jenny
J
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000150:complications / Q000473:pathology* / Q000517:prevention & control; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D014635:Valproic Acid