2015 Jul 22. pii: S0092-8674(15)00826-0. doi: 10.1016/j.cell.2015.06.056. [Epub ahead of print]
Anderson GR1, Aoto J2, Tabuchi K3, Földy C1, Covy J2, Yee AX4, Wu D1, Lee SJ2, Chen L4, Malenka RC5, Südhof TC6.
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Copyright © 2015 Elsevier Inc. All rights reserved.
- PMID:
- 26213384
- [PubMed – as supplied by publisher]