Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior.
Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
Departments of Neurology and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390-8813, USA.
Jacqueline
J
Blundell
Cory A
CA
Blaiss
Mark R
MR
Etherton
Felipe
F
Espinosa
Katsuhiko
K
Tabuchi
Christopher
C
Walz
Marc F
MF
Bolliger
Thomas C
TC
Südhof
Craig M
CM
Powell
D000818:Animals; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D002540:Cerebral Cortex / Q000502:physiology; D003342:Corpus Striatum / Q000502:physiology; D003523:Cycloserine / Q000494:pharmacology; D054333:Drug Partial Agonism; D019706:Excitatory Postsynaptic Potentials; D006120:Grooming; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation; D018782:Maze Learning; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D012919:Social Behavior; D013037:Spatial Behavior; D013239:Stereotyped Behavior; D013569:Synapses / Q000502:physiology
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C093438:neuroligin 1; D003523:Cycloserine