Journal
CELL
Volume 162, Issue 3, Pages 593-606Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.06.056
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Funding
- NIH [R37 MH052804, K99 MH103531, P50 MH086403]
- Autism Speaks [7953]
- Grants-in-Aid for Scientific Research [25282242] Funding Source: KAKEN
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alpha- and beta-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that, although beta-neurexins are expressed at much lower levels than alpha-neurexins, conditional knockout of beta-neurexins with continued expression of alpha-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The beta-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 beta-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 beta-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic beta-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for beta-neurexins in the endocannabinoid-dependent regulation of neural circuits.
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