title: β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling.
abstract: α- and β-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that, although β-neurexins are expressed at much lower levels than α-neurexins, conditional knockout of β-neurexins with continued expression of α-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The β-neurexin knockout phenotype was attenuated by CB1-receptor inhibition, which blocks presynaptic endocannabinoid signaling, or by 2-arachidonoylglycerol synthesis inhibition, which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of β-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of β-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic β-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for β-neurexins in the endocannabinoid-dependent regulation of neural circuits.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Garret R
authors.initials: GR
authors.lastname: Anderson
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Aoto
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Department of Neurophysiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tabuchi
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Földy
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Covy
authors.affiliation: Department of Neurosurgery, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Ada Xin
authors.initials: AX
authors.lastname: Yee
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Dick
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Nancy Pritzker Laboratory, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA; Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA. Electronic address: tcs1@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D063388:Endocannabinoids / Q000096:biosynthesis / Q000378:metabolism*; D005989:Glycerides / Q000096:biosynthesis; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D002135:Calcium-Binding Proteins; D063388:Endocannabinoids; D005989:Glycerides; D019006:Neural Cell Adhesion Molecules; D018377:Neurotransmitter Agents; C527193:Nrxn1 protein, mouse; C094503:glyceryl 2-arachidonate; D002118:Calcium