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.HighlightsIn 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.

Loss of Reelin suppresses cell survival and mobility in non-Hodgkin lymphoma

“…It was reported that Reelin has two major receptors: ApoER2 (apolipoprotein E receptor 2) and NMDAR (N-methyli-D aspartate receptor) to transfer signals. Notch1 could function as a postsynaptic receptor with functional interactions with these two receptors (41,42). Loss of Notch1 results in suppressing glutamatergic transmission and leads to decreased cAMP response element-binding signaling (42).…”

“…Notch1 could function as a postsynaptic receptor with functional interactions with these two receptors (41,42). Loss of Notch1 results in suppressing glutamatergic transmission and leads to decreased cAMP response element-binding signaling (42). Increased intracellular content of cAMP is closely related with the apoptosis of lymphocytes (30,31).…”

Intra-day variations of blood reelin levels in healthy individuals

“…Thereby RELN is crucial for synaptic plasticity and learning processes. Reelin-deficient mice show severe deficits in long-term potentiation and cognitive learning [15][16][17][18][19][20][21].…”

Jagged1 Is Altered in Alzheimer's Disease and Regulates Spatial Memory Processing

“…Our group has previously shown that the loss of Notch1 from the CA1 subfield of the hippocampus of mice results in a significant impairment in LTP and LTD and a considerable deficit in hippocampus-dependent spatial memory. Furthermore, at a mechanistic level, we have shown that in the absence of Notch1, NMDA currents are significantly reduced and downstream activation of cAMP response element binding (CREB) protein is profoundly affected (Brai et al, 2015 ), likely accounting for the plasticity deficit. The Notch1-CREB axis has been prevously reported in fruit flies, where Notch1 protein has been shown to be essential for CREB hyperphosphorylation and its subsequent activation (Zhang et al, 2013 ).…”