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Cell. 2015 Jul 30;162(3):593-606. doi: 10.1016/j.cell.2015.06.056. Epub 2015 Jul 23.

β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling.

Author information

1
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.
2
Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
3
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.
4
Department of Neurosurgery, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305-5453, USA.
5
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.
6
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.

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.

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PMID:
26213384
PMCID:
PMC4709013
DOI:
10.1016/j.cell.2015.06.056
[Indexed for MEDLINE]
Free PMC Article

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