Disrupting Jagged1–Notch signaling impairs spatial memory formation in adult mice

• Notch signaling is important in brain development and implicated in adult synaptic plasticity and memory.
• Roles of Notch ligands (e.g., Delta-like, Dll1, Jagged, Jag1), modulators (Lunatic fringe, Lfng) in memory are unknown.
• We examined memory and other behaviors in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 + Lfng.
• Mice with reduced Jag1 expression showed impaired spatial memory formation but normal behavior in all other tests.
• These results provide the first in vivo evidence that Jag1–Notch signaling is critical for memory formation in adults.

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1+/−) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1–Notch signaling is critical for memory formation in the adult brain.