Neuroligins Sculpt Cerebellar Purkinje-Cell Circuits by Differential Control of Distinct Classes of Synapses.
Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo.
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA.
Bo
B
Zhang
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA.
Lulu Y
LY
Chen
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
Xinran
X
Liu
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA.
Stephan
S
Maxeiner
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA.
Sung-Jin
SJ
Lee
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA.
Ozgun
O
Gokce
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Room G1021, Stanford, CA 94305, USA. Electronic address: tcs1@stanford.edu.
Thomas C
TC
Südhof
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D013569:Synapses / Q000145:classification* / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D009419:Nerve Tissue Proteins; C098003:neuroligin 2