title: Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.
abstract: The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.
authors.affiliation: Department of Anesthesiology National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan,.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yufune
authors.affiliation: Department of Anesthesiology National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan,.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Anesthesiology National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan,.
authors.forename: Isao
authors.initials: I
authors.lastname: Takamatsu
authors.affiliation: Department of Physiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Anesthesiology National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan,.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Takaenoki
authors.affiliation: Institute for Research on Cancer and Aging (IRCAN), University of Nice Sophia Antipolis, Centre Antoine Lacassagne, 33 Avenue de Valombrose, Nice 06189, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.affiliation: 1] Institute for Research on Cancer and Aging (IRCAN), University of Nice Sophia Antipolis, Centre Antoine Lacassagne, 33 Avenue de Valombrose, Nice 06189, France [2] Centre Scientifique de Monaco (CSM) Biochemical Department, 8 Quai Antoine Ier, MC 98000, Monaco.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.affiliation: Aging Regulation Research Team, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Anesthesiology National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan,.
authors.forename: Tomiei
authors.initials: T
authors.lastname: Kazama
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001321:Autistic Disorder / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000032:analysis; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000032:analysis
chemical_list: D020033:Protein Isoforms; C424127:SL 327; D000607:Aminoacetonitrile; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3