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

Hauser, David; Behr, Katharina; Konno, Kohtarou; Schreiner, Dietmar; Schmidt, Alexander; Watanabe, Masahiko; Bischofberger, Josef; Scheiffele, Peter

doi:10.1016/j.neuron.2022.04.017

Cited by 23 publications

(37 citation statements)

References 107 publications

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“…The function of Nrxns can be influenced by alternative exon usage (Aoto et al, 2013;Dai et al, 2019Dai et al, , 2021, synaptic localization (Hauser et al, 2022), and ligand availability (Uchigashima et al, 2020a). Nrxn alternative splicing varies among classes of hippocampal interneurons, which may 10.3389/fnsyn.2022.1087238 result in the formation of different trans-synaptic complexes to differentially sculpt synaptic transmission onto principal neurons (Fuccillo et al, 2015;Nguyen T. -M. et al, 2016;Uchigashima et al, 2020a).…”

Section: Conclusion From Functional Studies Of Neurexinsmentioning

confidence: 99%

“…Unique to Nrxn3 is the presence of an in-frame stop codon encoded in the SS5 exon (Nrxn3 SS5+), that results in the production of Nrxn3 without transmembrane and intracellular domains ( Ushkaryov and Südhof, 1993 ; Tabuchi and Südhof, 2002 ). This truncated splice isoform of Nrxn3 is post-translationally modified by the addition of a glycosylphosphatidylinositol (GPI) membrane anchor ( Hauser et al, 2022 ). The GPI membrane anchor attaches the extracellular sequences of Nrxn3 to the plasma membrane but does not permit intracellular signaling.…”

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

“…Furthermore, the Nrxn3 SS5 exon encodes for mRNA sequences that are subject to strong translational repression resulting in cell-type specific protein expression. Nrxn3 SS5+ mRNA is detected in pyramidal neurons and GABAergic neurons in hippocampus but its protein is only detected in inhibitory neurons ( Hauser et al, 2022 ).…”

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

“…Measuring the expression and localization of Nrxn protein is no easy task due to the lack of antibodies that detect individual Nrxns ( Südhof, 2017 ). Currently, the most reliable approach to characterize Nrxn protein requires the generation of endogenously tagged Nrxns ( Anderson et al, 2015 ; Ribeiro et al, 2019 ; Trotter et al, 2019 ; Klatt et al, 2021 ; Hauser et al, 2022 ). However, analysis of Nrxn expression at the protein level and its targeting to specific synapses will be an important undertaking for future studies.…”

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

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Neurexins and their ligands at inhibitory synapses

Boxer

Aoto

2022

Front. Synaptic Neurosci.

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Since the discovery of neurexins (Nrxns) as essential and evolutionarily conserved synaptic adhesion molecules, focus has largely centered on their functional contributions to glutamatergic synapses. Recently, significant advances to our understanding of neurexin function at GABAergic synapses have revealed that neurexins can play pleiotropic roles in regulating inhibitory synapse maintenance and function in a brain-region and synapse-specific manner. GABAergic neurons are incredibly diverse, exhibiting distinct synaptic properties, sites of innervation, neuromodulation, and plasticity. Different classes of GABAergic neurons often express distinct repertoires of Nrxn isoforms that exhibit differential alternative exon usage. Further, Nrxn ligands can be differentially expressed and can display synapse-specific localization patterns, which may contribute to the formation of a complex trans-synaptic molecular code that establishes the properties of inhibitory synapse function and properties of local circuitry. In this review, we will discuss how Nrxns and their ligands sculpt synaptic inhibition in a brain-region, cell-type and synapse-specific manner.

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Section: Conclusion From Functional Studies Of Neurexinsmentioning

confidence: 99%

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

Section: Region and Cell-type Specific Expression Of Neurexinsmentioning

confidence: 99%

See 2 more Smart Citations

Neurexins and their ligands at inhibitory synapses

Boxer

Aoto

2022

Front. Synaptic Neurosci.

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“…Moreover, the high degree of splicing regulation in the brain is accompanied by the expression of a large number of neuronal splicing regulators 18 . Recent rodent studies mapped developmental and cell type-specific alternative splicing programs in neurons 14,19-24 . The targets of such regulation are enriched for risk genes associated with neurodevelopmental disorders 19,25 and alterations in splicing events are associated with autism spectrum disorders in the human population 26-28 .…”

Section: Introductionmentioning

confidence: 99%

Trans-cellular control of synapse properties by a cell type-specific splicing regulator

Schulz

Ortiz

Feng

et al. 2022

Preprint

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The recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. 'Terminal selector' transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. Focusing on hippocampal pyramidal cells and SST-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.

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Revisiting the development of cerebellar inhibitory interneurons in the light of single-cell genetic analyses

Schilling

2023

Histochem Cell Biol

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The present review aims to provide a short update of our understanding of the inhibitory interneurons of the cerebellum. While these cells constitute but a minority of all cerebellar neurons, their functional significance is increasingly being recognized. For one, inhibitory interneurons of the cerebellar cortex are now known to constitute a clearly more diverse group than their traditional grouping as stellate, basket, and Golgi cells suggests, and this diversity is now substantiated by single-cell genetic data. The past decade or so has also provided important information about interneurons in cerebellar nuclei. Significantly, developmental studies have revealed that the specification and formation of cerebellar inhibitory interneurons fundamentally differ from, say, the cortical interneurons, and define a mode of diversification critically dependent on spatiotemporally patterned external signals. Last, but not least, in the past years, dysfunction of cerebellar inhibitory interneurons could also be linked with clinically defined deficits. I hope that this review, however fragmentary, may stimulate interest and help focus research towards understanding the cerebellum.

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

Cited by 23 publications

References 107 publications

Neurexins and their ligands at inhibitory synapses

Neurexins and their ligands at inhibitory synapses

Trans-cellular control of synapse properties by a cell type-specific splicing regulator

Revisiting the development of cerebellar inhibitory interneurons in the light of single-cell genetic analyses

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