Notch for Neuronal Activity

Science Signaling  15 Feb 2011:
Vol. 4, Issue 160, pp. ec45
DOI: 10.1126/scisignal.4160ec45

Binding of ligand to the transmembrane receptor Notch triggers a series of secretase-mediated cleavage events that culminate in the generation of the Notch intracellular domain (NICD), which translocates to the nucleus to transcriptionally activate target genes. Notch signaling has well-established roles in neuronal development and progenitor fate specification. Two groups have defined roles for Notch signaling in responses to olfactory stimulation in Drosophila and in promoting synaptic plasticity in mouse hippocampal neurons. Lieber et al. monitored Notch activity in Drosophila through the use of chimeric forms of Notch, with a transcriptional activator substituted for the cytosolic domain that, when cleaved from the Notch chimera, drives transcription of destabilized green fluorescent protein (GFP). They found that prolonged odorant exposure activated Notch in olfactory receptor neurons (ORNs). Notch signaling was detected in distinct patterns of ORNs in response to different odors and, in the case of geranyl acetate and CO2, was detected in the ORNs known to respond to those odors. Odorant-mediated activation of Notch required the ligand Delta (as determined by the use of flies bearing temperature-sensitive loss-of-function mutations in Delta), the activity of odorant receptors (as determined by expressing exogenous odorant receptors in different ORNs), and synaptic transmission (as determined through the use of flies that expressed tetanus toxin light chain). Because Delta activates Notch in trans, the authors proposed that synaptic transmission from activated ORNs could induce production of Delta in neighboring glial cells.

In the mammalian brain, expression of the gene Arc (activity-regulated, cytoskeleton-associated; also known as Arg3.1) is induced by increased neuronal activity. In a second paper, Alberi et al. found that the distribution of Arc and NICD overlapped, suggesting that Notch1 signaling occurred in active hippocampal neurons. Changes in NICD abundance correlated with changes in neuronal activity, and neuronal activity also increased the abundance of Notch1 and the abundance of Jag1, which encodes a Notch ligand. Mice that explored a novel environment had increased numbers of neurons that stained for Arc1 or Notch1, and most of the Arc1-positive neurons had Notch1 in the nuclei. Arc-null mice showed decreased NICD abundance and no increase in Notch1 abundance in response to exploration of a novel environment. Arc mutant neurons showed decreased abundance of NICD1; rescuing this phenotype required the ability of Arc to bind to endophilin. Notch processing requires endocytosis through a dynamin-driven process, and Arc and dynamin coimmunoprecipitated from cortical extracts. Hippocampal slices from mice with a conditional, postnatal deletion of Notch1 in the hippocampus (Notch1 cKO) showed decreased long-term potentiation (LTP) compared with those from wild-type mice. Furthermore, Notch cKO mice had cognitive and memory deficits. Thus, Notch activation occurs in response to neuronal activity in Drosophila ORNs and promotes synaptic plasticity in mouse brain.

T. Lieber, S. Kidd, G. Struhl, DSL-Notch signaling in the Drosophila brain in response to olfactory stimulation. Neuron 69, 468–481 (2011). [Online Journal]

L. Alberi, S. Liu, Y. Wang, R. Badie, C. Smith-Hicks, J. Wu, T. J. Pierfelice, B. Abazyan, M. P. Mattson, D. Kuhl, M. Pletnikov, P. F. Worley, N. Gaiano, Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 69, 437–444 (2011). [Online Journal]