Alternative Splicing of Presynaptic Neurexins Differentially Controls Postsynaptic NMDA and AMPA Receptor Responses

Jinye Dai; Jason Aoto; Thomas C Südhof

doi:10.1016/j.neuron.2019.03.032

Alternative Splicing of Presynaptic Neurexins Differentially Controls Postsynaptic NMDA and AMPA Receptor Responses

Neuron. 2019 Jun 5;102(5):993-1008.e5. doi: 10.1016/j.neuron.2019.03.032. Epub 2019 Apr 17.

Authors

Jinye Dai¹, Jason Aoto², Thomas C Südhof³

Affiliations

¹ Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
² Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
³ Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA. Electronic address: tcs1@stanford.edu.

Abstract

AMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4- splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.

Keywords: AMPA receptor; NMDA receptor; alternative splicing; epigenetics; long-term potentiation; memory; neurexins; neuroligin; schizophrenia; subiculum; synapse formation; synaptic transmission.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alternative Splicing / genetics*
Animals
Calcium-Binding Proteins / genetics*
Calcium-Binding Proteins / metabolism
Gene Knock-In Techniques
Hippocampus / metabolism*
Mice
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Neural Cell Adhesion Molecules / genetics*
Neural Cell Adhesion Molecules / metabolism
RNA Splice Sites
Receptors, AMPA / metabolism*
Receptors, N-Methyl-D-Aspartate / metabolism*
Synapses / metabolism*

Substances

Calcium-Binding Proteins
Nerve Tissue Proteins
Neural Cell Adhesion Molecules
Nrxn1 protein, mouse
RNA Splice Sites
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
neurexin 3, mouse
neurexin II
neurexin IIIbeta
neurexin Ibeta

Abstract

Publication types

MeSH terms

Substances

Grants and funding