Learning and memory deficits in Notch mutant mice.
Notch is a critical component of evolutionarily conserved signaling mechanisms that regulate development and may contribute to plasticity-related processes, including changes in neurite structure and maintenance of neural stem cells. Deficits in the Notch pathway are responsible for Alagille and Cadasil syndromes, which are associated with mental retardation and dementia. Additionally, in postmitotic neurons, Notch proteins interact with presenilins and with beta-amyloid precursor protein and could therefore have a role in the memory deficits associated with familial and sporadic Alzheimer's disease. To test if alterations in Notch signaling can lead to learning and memory deficits, we studied mice with mutations in this pathway. Here, we show that null heterozygous mutations in Notch1 result in deficits in spatial learning and memory without affecting other forms of learning, motor control, or exploratory activity. We also show that null heterozygous mutations in the downstream cofactor RBP-J result in similarly specific spatial learning and memory deficits. These data indicate that a constitutive decrease in Notch signaling can result in specific learning and memory deficits and suggest that abnormalities in Notch-dependent transcription may contribute to the cognitive deficits associated with Alzheimer's disease and Alagille and Cadasil syndromes.
Costa
Rui M
RM
University of California, Los Angeles, Department of Neurobiology, and Brain Research Institute, 695 Young Drive South, Room 2554, Box 951761, Los Angeles, CA 90095-1761, USA.
Honjo
Tasuku
T
Silva
Alcino J
AJ
D000704:Analysis of Variance; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains / Q000502:physiology / Q000523:psychology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013037:Spatial Behavior / Q000502:physiology*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors