title: Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4.
abstract: Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4-/- mice fail to form neuromuscular synapses and die at birth. Lrp4-/- mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3-CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or auto-antibodies to Lrp4 should be evaluated for neurological deficits.
authors.affiliation: Graduate Program in Developmental Genetics, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: Graduate Program in Developmental Genetics, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Froemke
authors.affiliation: Graduate Program in Developmental Genetics, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D003071:Cognition; D049229:Dendritic Spines / Q000378:metabolism; D026502:LDL-Receptor Related Proteins; D017774:Long-Term Potentiation; D018782:Maze Learning; D008566:Membranes / Q000378:metabolism; D008568:Memory; D008817:Mice, Mutant Strains; D009132:Muscles / Q000378:metabolism; D009473:Neuronal Plasticity; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D011973:Receptors, LDL
keywords: behavior; hippocampus; learning; long-term potentiation; low-density lipoprotein-related receptor; mouse; neuroscience; synapse