Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner

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Abstract

At CA1→subiculum synapses, alternatively spliced neurexin-1 (Nrxn1^SS4+) and neurexin-3 (Nrxn3^SS4+) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without affecting synapse formation. Nrxn1^SS4+ and Nrxn3^SS4+ act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1 receptors. Whether neurexin-Cbln2-GluD1 signaling has additional functions besides regulating NMDA- and AMPA-receptors, and whether such signaling performs similar roles at other synapses, however, remains unknown. Here, we demonstrate using constitutive Cbln2 deletions in mice that at CA1→subiculum synapses, Cbln2 performs no additional developmental roles besides regulating AMPA- and NMDA-receptors. Moreover, low-level expression of functionally redundant Cbln1 did not compensate for a possible synapse-formation function of Cbln2 at CA1→subiculum synapses. In exploring the generality of these findings, we examined the prefrontal cortex where Cbln2 was recently implicated in spinogenesis, and the cerebellum where Cbln1 is known to regulate parallel-fiber synapses. In the prefrontal cortex, Nrxn1^SS4+-Cbln2 signaling selectively controlled NMDA-receptors without affecting spine or synapse numbers, whereas Nrxn3^SS4+-Cbln2 signaling had no apparent role. In the cerebellum, conversely, Nrxn3^SS4+-Cbln1 signaling regulated AMPA-receptors, whereas now Nrxn1^SS4+-Cbln1 signaling had no manifest effect. Thus, Nrxn1^SS4+- and Nrxn3^SS4+-Cbln1/2 signaling complexes differentially control NMDA- and AMPA-receptors in different synapses in diverse neural circuits without regulating synapse or spine formation.

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All numerical data and P values within this study have been included in the manuscript.

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Jinye Dai

Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, United States

For correspondence
jinye.dai@mssm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8497-3154
Kif Liakath-Ali

Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9047-7424
Samantha Rose Golf

Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Thomas C Südhof

Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, United States

For correspondence
tcs1@stanford.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3361-9275

Funding

National Institute of Mental Health (MH052804)

Thomas C Südhof

European Molecular Biology Organization (ALTF 803-2017)

Kif Liakath-Ali

Larry L. Hillblom Foundation (2020-A-016-FEL)

Kif Liakath-Ali

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse studies were performed according to protocols (#18846) approved by the Stanford University Administrative Panel on Laboratory Animal Care.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.