Spatio-molecular domains identified in the mouse subthalamic nucleus and neighboring glutamatergic and GABAergic brain structures

Wallén-Mackenzie, Åsa; Dumas, Sylvie; Papathanou, Maria; Martis, Mihaela M.; Vlcek, Bianca; König, Niclas; Björklund, Åsa K.

doi:10.1038/s42003-020-1028-8

Cited by 46 publications

(68 citation statements)

References 54 publications

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“…At the cluster level, we found 923 isoforms from 823 genes exhibiting isoform shifts among the 48 clusters passing filter despite constant gene abundance (Supplementary Table 3). Another isoform of note that marks the L6b Ror1_ 1 cluster, a subset of cells in the L6b subclass, is the Stxbp2-207 isoform whose gene Stxbp2 has previously been detected in the subthalamic nucleus and the posterior hypothalamus 36 .…”

Section: Articlementioning

confidence: 99%

Isoform cell-type specificity in the mouse primary motor cortex

Booeshaghi

Yao

Velthoven

et al. 2021

Nature

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Full-length SMART-seq1 single-cell RNA sequencing can be used to measure gene expression at isoform resolution, making possible the identification of specific isoform markers for different cell types. Used in conjunction with spatial RNA capture and gene-tagging methods, this enables the inference of spatially resolved isoform expression for different cell types. Here, in a comprehensive analysis of 6,160 mouse primary motor cortex cells assayed with SMART-seq, 280,327 cells assayed with MERFISH2 and 94,162 cells assayed with 10x Genomics sequencing3, we find examples of isoform specificity in cell types—including isoform shifts between cell types that are masked in gene-level analysis—as well as examples of transcriptional regulation. Additionally, we show that isoform specificity helps to refine cell types, and that a multi-platform analysis of single-cell transcriptomic data leveraging multiple measurements provides a comprehensive atlas of transcription in the mouse primary motor cortex that improves on the possibilities offered by any single technology.

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Section: Articlementioning

confidence: 99%

Isoform cell-type specificity in the mouse primary motor cortex

Booeshaghi

Yao

Velthoven

et al. 2021

Nature

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“…To test this, we evaluated the transcript expression levels of Pvalb, Gad1 and Slc32a1, which are coexpressed with Cdh23 in subthalamic region [33], from knock-in mice and control littermates. However, we did not observe any significant differences in the transcript expression levels of these genes (Supplementary Figure 7B), which might be attributable to bulk sampling from the distinct molecular domains of subthalamic region with heterogeneous cell types [34].…”

Section: Potential Role Of the Cdh23 C753g>a Variant In Cdh23 Transcript Expressionmentioning

confidence: 62%

Role of an Atypical Cadherin Gene,Cdh23in Prepulse Inhibition and Implication ofCDH23in Schizophrenia

Balan

Ohnishi

Watanabe

et al. 2020

Preprint

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We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. The extremely high logarithm of odds (LOD) score of the chromosome-10 QTL suggests the presence of additional causative gene(s). Here, we reanalyzed the previously reported QTLs with increased marker density. The highest LOD score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Therefore, we examined the roles of Cdh23 and c.753G>A in PPI. The Cdh23 gene was shown to be expressed in brain regions relevant for sensorimotor gating. We engineered the c.753G (C3H) allele into the B6 genetic background, which dampened PPI without affecting hearing acuity. An e-QTL (expression-QTL) effect imparted by the c.753G>A variant for the Cdh23 transcript in the brain was also revealed. The syntenous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the data in the present study reveal a PPI-regulating Cdh23 variant and a possible contribution of this gene to schizophrenia susceptibility.

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“…The STN as a whole innervates all other BG nuclei, as well as discrete parts of midbrain, brainstem, thalamus and cerebral cortex (Smith et al, 1998; Emmi et al, 2020). Because STN neurons exhibit markedly heterogeneous structural (axonal), physiological and molecular properties (Bevan et al, 2000; Sato et al, 2000; Koshimizu et al, 2013; Wallén-Mackenzie et al, 2020), it seems unlikely that all STN neurons innervate all of these diverse targets. It is currently unclear whether all STN neurons innervating striatum also innervate, via axon collaterals, one or more other BG nuclei.…”

Section: Discussionmentioning

confidence: 99%

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

Kondabolu

Doig

Ayeko

et al. 2020

Preprint

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The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

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Spatio-molecular domains identified in the mouse subthalamic nucleus and neighboring glutamatergic and GABAergic brain structures

Cited by 46 publications

References 54 publications

Isoform cell-type specificity in the mouse primary motor cortex

Isoform cell-type specificity in the mouse primary motor cortex

Role of an Atypical Cadherin Gene,Cdh23in Prepulse Inhibition and Implication ofCDH23in Schizophrenia

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

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