Dab1 is required for synaptic plasticity and associative learning.
Disabled-1 (Dab1) is an adaptor protein that is an obligate effector of the Reelin signaling pathway, and is critical for neuronal migration and dendrite outgrowth during development. Components of the Reelin pathway are highly expressed during development, but also continue to be expressed in the adult brain. Here we investigated in detail the expression pattern of Dab1 in the postnatal and adult forebrain, and determined that it is expressed in excitatory as well as inhibitory neurons. Dab1 was found to be localized in different cellular compartments, including the soma, dendrites, presynaptic and postsynaptic structures. Mice that are deficient in Dab1, Reelin, or the Reelin receptors ApoER2 and VLDLR exhibit severely perturbed brain cytoarchitecture, limiting the utility of these mice for investigating the role of this signaling pathway in the adult brain. In this study, we developed an adult forebrain-specific and excitatory neuron-specific conditional knock-out mouse line, and demonstrated that Dab1 is a critical regulator of synaptic function and hippocampal-dependent associative and spatial learning. These dramatic abnormalities were accompanied by a reduction in dendritic spine size, and defects in basal and plasticity-induced Akt and ERK1/2 signaling. Deletion of Dab1 led to no obvious changes in neuronal positioning, dendrite morphology, spine density, or synaptic composition. Collectively, these data conclusively demonstrate an important role for Reelin-Dab1 signaling in the adult forebrain, and underscore the importance of this pathway in learning and memory.
Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, Department of Cell Biology and Neuroscience and Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, and Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037.
Justin
J
Trotter
Gum Hwa
GH
Lee
Tatiana M
TM
Kazdoba
Beth
B
Crowell
Jason
J
Domogauer
Heather M
HM
Mahoney
Santos J
SJ
Franco
Ulrich
U
Müller
Edwin J
EJ
Weeber
Gabriella
G
D'Arcangelo
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D007858:Learning; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; D051057:Proto-Oncogene Proteins c-akt; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases