title: Disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.
abstract: It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain.
authors.affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada M5G 1X8.
authors.forename: Derya
authors.initials: D
authors.lastname: Sargin
authors.forename: Leigh C P
authors.initials: LC
authors.lastname: Botly
authors.forename: Gemma
authors.initials: G
authors.lastname: Higgs
authors.forename: Alexander
authors.initials: A
authors.lastname: Marsolais
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D013028:Space Perception / Q000502:physiology*
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; C559657:Dlk2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016695:Glycosyltransferases; C498392:Lfng protein, mouse