However, interpretation of such findings is complicated by the fact that the manipulations of isoforms were conducted in cells where endogenous isoform repertoires were unknown.
#Mouse hippocampus anatomy slm code#
Based on ectopic expression and knock-out experiments in mice it has been postulated that neurexin isoforms might contribute to an alternative splice code for selective synaptic interactions and differ in their tethering at neuronal synapses ( Boucard et al., 2005 Chih et al., 2006 Graf et al., 2006 Fu and Huang, 2010 Futai et al., 2013 Aoto et al., 2015 Traunmüller et al., 2016). Importantly, individual splice insertions in the neurexin proteins control biochemical interactions with an array of synaptic ligands ( Baudouin and Scheiffele, 2010 Reissner et al., 2013).
However, the actual alternative exon incorporation rates in interneuron and principal neuron populations have not been examined. Pairwise comparisons of relative transcript levels recovered from single cells suggested that individual cells within one cell type might exhibit more similar alternative exon usage than cells from divergent origins ( Fuccillo et al., 2015). This indicated that at least some neurexin isoforms are enriched in a cell type-specific manner. Isoform diversity scales with the cellular complexity of brain regions and one purified cell population was shown to be strongly enriched for a subset of isoforms ( Schreiner et al., 2014a). Through the use of alternative promoters (alpha and beta) and alternative splicing at up to six alternatively spliced segments (AS1-6) more than 1300 transcripts are generated that are expressed in the mature mouse nervous system ( Schreiner et al., 2014a Treutlein et al., 2014 Schreiner et al., 2015). Neurexins ( Nrxn1,2,3) represent one gene family of highly diversified synaptic adhesion molecules. However, given the difficulty of mapping endogenous splice isoform repertoires it is poorly understood how splice isoforms are differentially distributed across neuronal cell types. Gene families encoding large numbers of isoforms generated through multiple genes, alternative promoters and extensive alternative splicing, hold the potential to generate recognition tags for specific trans-synaptic interactions ( Baudouin and Scheiffele, 2010 Reissner et al., 2013 Takahashi and Craig, 2013 Schreiner et al., 2014b Li et al., 2015). For example, synaptic partners express matching pairs of adhesive factors or afferents are repelled from inappropriate targets through chemorepulsive signaling molecules ( Sanes and Yamagata, 2009 Shen and Scheiffele, 2010). A large degree of this structural and functional specificity is thought to be genetically encoded. Specific synaptic connectivity and function are essential for the appropriate operation of neuronal circuits. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit function Introduction Conditional ablation of Nrxn alternative splice insertions selectively in PV + cells results in elevated hippocampal network activity and impairment in a learning task. 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. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. 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. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits.