Notch to remember Rui M. Costa 1,2 , Camilla Drew 1 and Alcino J. Silva 1 1 Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, UCLA, 695 Young Drive South, Room 2554, Box 951761, Los Angeles, CA 90095-1761, USA 2 Present address: Department of Neurobiology, Duke University, Bryan Research Building, Room 333, Box 3209, 101 Research Drive, Durham, NC 27710, USA Some of the signaling molecules required for formation of long-term memories are involved primarily in adult brain function, but others participate in a variety of other biological processes. The Notch signaling pathway, which is important for cell fate specification and differentiation in various systems, is also active in the mature brain. Here, we review evidence from recent studies indicating that Notch signaling is required for formation of long-term memories, and discuss possible memory processes modulated by this pathway. We also consider the possible involvement of Notch signaling in cognitive disorders. Introduction What molecular mechanisms does the nervous system use in the formation of long-lasting memories? Did evolution select a unique set of molecules devoted exclusively to postmitotic neuronal signaling, or did it use sets of gene networks already employed in other processes, such as growth and differentiation? The evidence accumulated from molecular and cellular cognition studies suggests that both strategies were used. Some of the proteins involved in learning and memory, such as a-Ca 2C / calmodulin-dependent protein kinase II, are expressed almost exclusively in postnatal mature neurons [1]. Others, such as those of the Ras–mitogen-activated protein kinase (MAPK) signaling cascade, have several functions in the organism, from development and tumor formation to immunological and neuronal memory [2,3]. Molecules of the Notch pathway, which has been impli- cated in cell fate specification and differentiation in various systems [4–8], including tumor formation [9], are also expressed in postmitotic neurons [10–13]. Recent studies have implicated the Notch pathway in the formation of long-term memory [14–16]. Here, we review the evidence for a role of Notch signaling in the formation of long-lasting memories and discuss some possible roles of Notch in adult brain function. Notch is required for the formation of long-term memory Because the Notch pathway is crucial in many different stages of development, it is challenging to study the specific role of the Notch pathway in adult brain function. Two recent studies in Drosophila have circumvented this problem by using inducible Notch manipulations to demonstrate a crucial role of Notch in learning and memory [15,16]. Furthermore, these studies revealed that Notch is crucial specifically for the formation of long-term memories, but not for acquisition of new information or for short-term memory [15,16]. Activation of different temperature-sensitive Notch mutants caused specific impairments in long-term memory for Pavlovian olfactory conditioning [15,16] and conditional courtship [15]. These phenotypes did not seem to be caused by non- specific effects of the transgenes because they were temperature-dependent, and acquisition of the association or sensorimotor responses was not affected [15,16]. Involvement of Notch in long-term memory was further confirmed by inducible disruption of Notch signaling specifically in mushroom bodies using RNA interference [15]. Interestingly, disruption of Notch signaling seems to affect specifically the formation of long-term memory, but not another form of long-lasting memory called anesthesia- resistant memory [16]. Complementary studies in mam- mals confirm the findings of these Drosophila studies. For example, mice heterozygous for a null mutation in the gene encoding Notch1 (Notch1 C/– mice) display deficits in spatial learning in the hidden-platform version of the water maze [14]. In this training procedure, it was difficult to distinguish between deficits in short-term versus long-term memory, because the mice take several days to learn the spatial location of the escape platform. To circumvent this limitation, trained mice were taught to learn a new position of the platform, which they do readily, and then memory for this new position was tested at different times. Under these training conditions, it was possible to show that the mutant mice had intact short-term memory but deficient long-term memory [14] (Figure 1). This indicates that the long-term spatial memory deficits in the Notch1 C/– mutant mice were present despite normal acquisition and short-term spatial memory, and argues against a general deficit in hippo- campal development. Taken together, these studies suggest that, in both vertebrates and invertebrates, Notch signaling is crucial for long-term memory formation. Interestingly, it appears that Notch signaling can function as a bidirectional modulator of long-term memory formation, because induced overexpression of wild-type Notch can facilitate formation of long-term memory [16]. This finding raises the possibility that ligands of Notch receptors could be used in memory facilitation and as therapeutic aids for cognitive disorders. Corresponding author: Silva, A.J. (silvaa@mednet.ucla.edu). Available online 26 May 2005 Review TRENDS in Neurosciences Vol.28 No.8 August 2005 www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.05.003