An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus

Abstract
Article and author information

Abstract

The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. We here demonstrate that transcripts encoding the synaptic adhesion molecules neurexin-1,2,3 are commonly expressed in principal cells and interneurons of the mouse hippocampus but undergo highly differential, cell type-specific alternative splicing. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. By contrast, most parvalbumin-positive (PV⁺) interneurons lack Slm2, express a different neurexin splice isoform and co-express the corresponding splice isoform-specific neurexin ligand Cbln4. Conditional ablation of Nrxn alternative splice insertions selectively in PV⁺ cells results in elevated hippocampal network activity and impairment in a learning task. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit function

Article and author information

Author details

Thi-Minh Nguyen

Biozentrum, University of Basel, Basel, Switzerland

For correspondence
thi-minh.nguyen@unibas.ch

Competing interests
The authors declare that no competing interests exist.
Dietmar Schreiner

Biozentrum, University of Basel, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
Le Xiao

Biozentrum, University of Basel, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
Lisa Traunmüller

Biozentrum, University of Basel, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
Caroline Bornmann

Biozentrum, University of Basel, Basel, Switzerland

For correspondence
caroline.bornmann@unibas.ch

Competing interests
The authors declare that no competing interests exist.
Peter Scheiffele

Biozentrum, University of Basel, Basel, Switzerland

For correspondence
peter.scheiffele@unibas.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9516-9399

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Peter Scheiffele

European Research Council (SPLICECODE)

Peter Scheiffele

National Competence Centre for Research NCCR_SYNAPA

Peter Scheiffele

Innovative Medicines Initiatives, EU-AIMS

Peter Scheiffele

Boehringer Ingelheim Fonds

Lisa Traunmüller

Marie-Curie Mobility Fellowship European Union

Dietmar Schreiner

Werner Siemens/Opportunities in Excellence Fellowship

Thi-Minh Nguyen

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 animal procedures were reviewed and approved by the Kantonales Veterinäramt Basel-Stadt (Licence 2272). The Procedures were performed in strict accordance to the guidelines and every effort was mode to minimize suffering of the animals and to minimize animal numbers (either by replacement or optimization of procedures).

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.