Article

Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal Networks

Institute for Cell Engineering, Neuroregeneration Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron (Impact Factor: 15.05). 02/2011; 69(3):437-44. DOI: 10.1016/j.neuron.2011.01.004
Source: PubMed

ABSTRACT

Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation.

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    • "Interestingly, it appears that the reduction of Notch signaling affects sensory and memory processing[18]. Alberi et al. reported that conditional deletion of Notch1 in the postnatal hippocampus disrupted both LTP and LTD, and led to deficits in learning and short-term mem- ory[19]. Our data showed that NaHS was able to ameliorate the decrease expression of Jagged-1. "
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    • "and morphology, in the form of reduced LTP, LTD, and spine density. Consistent with these structural changes, these conditional knockout mice displayed significant behavioral deficits (Alberi et al., 2011). Collectively , these results demonstrate a conserved role for Notch in learning and memory and will likely expose new areas of investigation in the field of Notch signaling in neurons. "
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    • "That such an activity could also regulate F-actin is significant because studies in mice show that F-actin up regulation is important for memory formation and triggers the translocation of cytoskeleton-associated protein Arc/Arg3.1 into synapses (Lamprecht, 2011; Liu et al., 2012). Interestingly, Arc/Arg3.1 is required for proteolytic processing of Notch and synaptic plasticity (Alberi et al., 2011), which is consistent with our perspective that the sequence of activation of non-canonical and canonical Notch signaling might be important for LTM formation. Constitutive over-expression of either one of these activities might interfere with LTM formation. "
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