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.

Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709013/

See also:

http://drugprevent.org.uk/ppp/2018/08/endocannabinoid-mediates-excitatory-synaptic-function-of-%ce%b2-neurexins-commentary-%ce%b2-neurexins-control-neural-circuits-by-regulating-synaptic-endocannabinoid-signaling/

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