Neonatal Stroke in Mice Causes Long-Term Changes in Neuronal Notch-2 Expression That May Contribute to Prolonged Injury

Abstract

Background and Purpose— Notch receptors (1–4) are membrane proteins that, on ligand stilumation, release their cytoplasmic domains to serve as transcription factors. Notch-2 promotes proliferation both during development and cancer, but its role in response to ischemic injury is less well understood. The purpose of this study was to understand whether Notch-2 is induced after neonatal stroke and to investigate its functional relevance. Methods— P12 CD1 mice were subjected to permanent unilateral (right-sided) double ligation of the common carotid artery. Results— Neonatal ischemia induces a progressive brain injury with prolonged apoptosis and Notch-2 up-regulation. Notch-2 expression was induced shortly after injury in hippocampal areas with elevated c-fos activation and increased cell death. Long-term induction of Notch-2 also occurred in CA1 and CA3 in and around areas of cell death, and had a distinct pattern of expression as compared to Notch-1. In vitro oxygen glucose deprivation treatment showed a similar increase in Notch-2 in apoptotic cells. In vitro gain of function experiments, using an active form of Notch-2, show that Notch-2 induction is neurotoxic to a comparable extent as oxygen glucose deprivation treatment. Conclusions— These results suggest that Notch-2 up-regulation after neonatal ischemia is detrimental to neuronal survival.

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

“…Notch signaling has been hypothesized to have a causative role in brain damage following both acute insults, such as stroke, 14,15 as well as chronic neurodegenerative disorders such as AD. 31 Interestingly, excitotoxicity has been strongly implicated in the pathophysiology of both of these categories of disorders.…”

“…12 On the other hand, overactivation of Notch signaling, in response to hypoxic-ischemic or epileptic injury appears to contribute to neuronal demise. 14,15 Here we show that excitotoxic kainic acid (KA) treatment results in S-phase reentry with concomitant nuclear localization of Notch1. Notch signaling upon KA regulates Akt/Cyclind1 axis activation.…”

Notch signaling in the brain: In good and bad times

“…We, and others, have observed that under physiological condition, Hes1 and Hes5 expression (as readout of Notch-CSL signaling) appear unresponsive to changes in Notch activity (Alberi et al, 2011;Yu et al, 2001), whereas under ischemic condition there is a strong up-regulation of Notch/RBPJK targets (Alberi et al, 2010;Arumugam et al, 2006). We may speculate that, following injury, Notch undergoes rapid Importin-mediated trafficking and nuclear signaling is favored (Huenniger et al, 2010) (Fig.…”

“…Notch2 expression pattern is similar to Notch1, however, it is expressed at lower levels in cortical and hippocampal neurons as compared to Notch1 (Stump et al, 2002). Notch2 is also critically upregulated upon injury and appears to contribute to brain damage (Alberi et al, 2010;Ferrari Toninelli et al, 2003). Notch3 is mostly expressed in astroglial progenitors (Tanigaki et al, 2001), choroid plexus (Dang et al, 2006) and vasculature (Joutel et al, 2000), whereas Notch4 has, so far, not been detected.…”

“…Specifically in the hippocampus, Notch expression is induced by sensory experience and can behave as a novel "plasticity molecule": it is expressed postsynaptically and regulates spine morphology, synaptic plasticity and memory processing (Alberi et al, 2011;Costa et al, 2003;Wang et al, 2004). On the other hand, Notch1 is strongly induced following brain injury (Alberi et al, 2010;Arumugam et al, 2006) and may contribute to cell death. Notch2 expression pattern is similar to Notch1, however, it is expressed at lower levels in cortical and hippocampal neurons as compared to Notch1 (Stump et al, 2002).…”