Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling

摘要

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.

Keywords: Notch, ApoER2, NMDAR, CREB, plasticity, memory

Introduction

Cell to cell communication pathways, which regulate the development and patterning of the mammalian brain have been shown to play an important role in neuronal network function and memory encoding in the adult brain (Herz and Chen, ; Oliva et al., ; Marathe and Alberi, ). In particular, the signaling receptors, which are the substrates of the γ-secretase complex, represent a synaptic hub (De Strooper and Annaert, ; Parks and Curtis, ) and are implicated in the memory deficit associated with Alzheimer’s disease (AD; Haass and De Strooper, ; De Strooper et al., ). Notch and Reelin signaling, which are both under γ-secretase’s regulation, functionally converge in mediating cortical migration and dendritic patterning (Gaiano, ; Hashimoto-Torii et al., ). Furthermore, Notch1 and Reelin loss of function mouse models display similar plasticity defects and memory impairments (Herz and Chen, ; Alberi et al., ; Trotter et al., ), suggesting that these cascades may also crosstalk at mature synapses.Notch1 is a single-pass transmembrane receptor with an essential role in neural development (Gaiano and Fishell, ). Moreover, there is compelling evidence indicating that Notch1 has a critical role in adult brain function from invertebrates to mammals (Marathe and Alberi, ). Notch1 is expressed in the adult mammalian brain in neurons and stem cell niches (Stump et al., ). Activation of Notch1 occurs through binding to a specific ligand of the Delta Serrate ligand family, which is expressed on adjacent cells (Mumm et al., ). Upon ligand binding, the receptor can undergo sequential cleavage and generate the Notch intracellular domain (NICD; De Strooper et al., 1999), which has nuclear signaling function. NICD translocates to the nucleus and can bind to RBPJK inducing transcription of canonical targets (Kopan and Ilagan, 2009). Besides the canonical activity, there is mounting evidence that the Notch receptors display non-transcriptional functions, in a variety of cell types. The non-canonical signaling modality is achieved through the interaction with molecular players of other fundamental cellular cascades such as Abl, mTOR and Akt (Alberi et al., 2013). These crosstalks are just beginning to be understood and much less is known about Notch1 non-canonical signaling in neurons. Our own work has indicated that Notch1 processing is activity-dependent through the functional interaction with the early immediate gene Arc/Arg 3.1, which promotes γ-secretase’s activity (Alberi et al., 2011). Thus, sensory stimulation induces Notch activity in neuronal ensembles of the hippocampus and olfactory bulb (Alberi et al., 2011; Brai et al., 2014). As a result, Notch1 regulates synaptic plasticity and memory formation (Costa et al., 2003; Wang et al., 2004; Alberi et al., 2011). The mechanism underlying these functions has long been elusive and is the subject of the present study.In this work, we show that Notch1 functionally interacts with other postsynaptic receptors such as Apolipoprotein E receptor 2 (ApoER2) and N-methyl-D-aspartate receptor (NMDAR) and influences their function. In particular, loss of Notch1 results in decreased glutamatergic transmission leading to diminished cAMP response element-binding (CREB) signaling. This mechanism may explain the synaptic deficit observed in the Notch1 loss of function mice and strongly supports the role of Notch1 at the synapse. Further studies will address whether Notch1 alterations contribute to the memory impairment in humans.