β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling

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.