title: Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling.
abstract: Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia.
  
  
  CONCLUSIONS
  In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade.Notch1 regulates both NMDAR expression and composition.Notch1 influences a cascade of cellular events culminating in CREB activation.
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg Fribourg, Switzerland.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Brai
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg Fribourg, Switzerland.
authors.forename: Swananda
authors.initials: S
authors.lastname: Marathe
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne Lausanne, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Astori
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg Fribourg, Switzerland.
authors.forename: Naila Ben
authors.initials: NB
authors.lastname: Fredj
authors.affiliation: Histology Core Laboratory, Department of Cellular Biology and Anatomy, Georgia Health Sciences University Augusta, GA, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perry
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg Fribourg, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lamy
authors.affiliation: Institute of Anatomy, Faculty of Medicine, University of Bern Bern, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scotti
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg Fribourg, Switzerland ; Unit of Pathology, Department of Medicine, University of Fribourg Fribourg, Switzerland.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Alberi
keywords: ApoER2; CREB; NMDAR; Notch; memory; plasticity