Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition

Neuron. 2022 Jul 6;110(13):2094-2109.e10. doi: 10.1016/j.neuron.2022.04.017. Epub 2022 May 11.


The diversification of cell adhesion molecules by alternative splicing is proposed to underlie molecular codes for neuronal wiring. Transcriptomic approaches mapped detailed cell-type-specific mRNA splicing programs. However, it has been hard to probe the synapse-specific localization and function of the resulting protein splice isoforms, or "proteoforms," in vivo. We here apply a proteoform-centric workflow in mice to test the synapse-specific functions of the splice isoforms of the synaptic adhesion molecule Neurexin-3 (NRXN3). We uncover a major proteoform, NRXN3 AS5, that is highly expressed in GABAergic interneurons and at dendrite-targeting GABAergic terminals. NRXN3 AS5 abundance significantly diverges from Nrxn3 mRNA distribution and is gated by translation-repressive elements. Nrxn3 AS5 isoform deletion results in a selective impairment of dendrite-targeting interneuron synapses in the dentate gyrus without affecting somatic inhibition or glutamatergic perforant-path synapses. This work establishes cell- and synapse-specific functions of a specific neurexin proteoform and highlights the importance of alternative splicing regulation for synapse specification.

Keywords: GABA; RNA; alternative splicing; autism; interneuron; neuronal circuit; proteoform; synaptic adhesion; synaptic specificity; targeted proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing* / genetics
  • Animals
  • Cell Adhesion Molecules / metabolism
  • Mice
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / metabolism
  • Synapses / physiology


  • Cell Adhesion Molecules
  • Nerve Tissue Proteins
  • Protein Isoforms
  • RNA, Messenger