DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons
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ABSTRACT:
PROVIDER: PRJNA917294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22949950_1.fastq.gz | Fastqsanger.gz | |||
| SRR22949950_2.fastq.gz | Fastqsanger.gz | |||
| SRR22949951_1.fastq.gz | Fastqsanger.gz | |||
| SRR22949951_2.fastq.gz | Fastqsanger.gz | |||
| SRR22949952_1.fastq.gz | Fastqsanger.gz |
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Project description:Our group has reported that the histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation.
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Project description:The cortical plate (CP) is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, maturing postmitotic interneurons migrate during embryonic development over some distance to reach their final destination in the CP. The histone methyltransferase Disruptor of Telomeric Silencing 1-like (DOT1L) is necessary for proper CP development and layer distribution of glutamatergic neurons. However, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell autonomous manner. Deletion of Dot1l in Nkx2.1-expressing interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the CP from postnatal day 0 onwards. We observed an altered proportion of GABAergic interneurons in the cortex, with a significant decrease in parvalbumin-expressing interneurons. Moreover, a decreased number of mitotic cells at the embryonic day E14.5 was observed upon Dot1l deletion. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion result from premature cell cycle exit, but effects on postmitotic differentiation, maturation, and migration are likely at play as well.
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Project description:Since many years, we are interested in the regulation of the intraneuronal chloride concentration. We were the first group reporting a full knockout of the KCl-co-transporter KCC2, which dies immediately after birth due to respiratory failure. Notably, KCC2 loss-of-function mutations are associated with inherited febrile seizures, severe genetic generalized epilepsy and epilepsy of infancy with migrating focal seizures. Here, we used our floxed line to study the consequences of the disruption of KCC2 within parvalbumin-positive interneurons in mice. Remarkably, this leads to the disinhibition of PV-positive interneurons as evidenced by a decrease of E-S-Coupling and an increase in the sIPSC frequency. Nevertheless, these mice develop fatal epilepsy with progressive loss of parvalbumin-positive interneurons thus increasing network excitability.
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Project description:Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.
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Project description:Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during development is not well understood. The protracted maturation of these cells during postnatal development has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding hPSC-based disease modeling of their role in neuropsychiatric diseases. Here we present a cortical assembloid system that supports the development of PVALB+ cortical interneurons which match the molecular profiles of primary PVALB+ interneurons and display their distinctive electrophysiological features. Further, we characterized cortical interneuron development in a series of CRISPR-generated isogenic structural variants associated with schizophrenia and identified variant-specific phenotypes in cortical interneuron migration and the molecular profile of PVALB+ cortical interneurons. These findings reveal plausible mechanisms on how disruption of cortical interneuron development may impact schizophrenia risk and provide an exciting human experimental platform to facilitate the study of PVALB+ cortical interneurons.
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Project description:Cortical neurons are specified during embryonic development but often only acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the activity of the cerebral cortex. We found that the terminal differentiation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1a). Developmental loss of PGC-1a prevents PV+ interneurons from acquiring their unique structural, electrophysiological, synaptic, and metabolic features and disrupts PV+ interneuron subtype specification. PGC-1a exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRg and Mef2c. Our results uncover a molecular switch that translates neural activity into transcriptional programs promoting the maturation of PV+ interneurons at the appropriate developmental stage.
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Project description:Cortical neurons are specified during embryonic development but often only acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the activity of the cerebral cortex. We found that the terminal differentiation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1a). Developmental loss of PGC-1a prevents PV+ interneurons from acquiring their unique structural, electrophysiological, synaptic, and metabolic features and disrupts PV+ interneuron subtype specification. PGC-1a exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRg and Mef2c. Our results uncover a molecular switch that translates neural activity into transcriptional programs promoting the maturation of PV+ interneurons at the appropriate developmental stage.
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Project description:We hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the medial ganglionic eminence and diminish the population of parvalbumin+ and somatostatin+ cortical interneurons. Since Sonic Hedgehog promotes the production of cortical interneurons, we also postulated that the activation of Sonic Hedgehog signaling might restore neurogenesis, cortical interneuron population, and neurobehavioral function in premature newborns with IVH.
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Project description:Alzheimer’s disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimer’s disease, impaired metabolism and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimer’s disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we discovered early, sex-dependent alterations in parvalbumin-interneuron transcriptomic profiles. This corresponded with impaired parvalbumin-interneuron activity, which was sufficient to induce cognitive impairments and dysregulate retrosplenial functional connectivity. In fMRI scans from patients with mild cognitive impairment and Alzheimer’s disease, we observed a similar sex-dependent dysregulation of retrosplenial cortex functional connectivity and, in post-mortem tissue from subjects with Alzheimer’s disease, a loss of parvalbumin interneurons. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in the retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy.
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