Postnatal Arx transcriptional activity regulates functional properties of PV interneurons

Joseph, Donald J.; Deimling, Markus von; Hasegawa, Yuiko; Cristancho, Ana G.; Ahrens‐Nicklas, Rebecca C.; Rogers, Stephanie; Risbud, Rashmi; McCoy, Almedia J.; Marsh, Eric D.

doi:10.1016/j.isci.2020.101999

Cited by 15 publications

(15 citation statements)

References 100 publications

(98 reference statements)

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“…4H neurons did not show changes in activity upon treatment with the GABA antagonists, while control cells showed a significantly increased activity after treatment. As ARX was reported to have important roles in the Parvalbumin interneurons (39), we tested whether specific interneuron lineages were affected in 4H. Indeed QPCR analysis identified an increase in ERBB4, a marker for PV neurons, confirming other results that interneuron regulation may be affected in 4H.…”

Section: Discussionsupporting

confidence: 60%

“…Although only a small number of genes were differentially regulated in all cell types, an interesting finding was the decreased expression of ARX in cerebellar cells of 4H patients. Considering the important role of ARX in cortical neuronal development and migration(32, 33, 39), we studied GAD65/67 expression in patient tissue and showed an increase in GAD65/67 immunoreactivity confirming interneuron changes in the cortex of 4H patients. In iPSC-derived cortical neuron cultures, 4H cortical neurons also showed decreased expression of ARX and affected interneuron generation as measured by a decreased percentage of GABAergic synapses.…”

Section: Discussionmentioning

confidence: 84%

“…Loss of function mutations in ARX lead to pleiotropic disorders such as X-linked Lissencephaly with Ambigious Genitalia (XLAG, OMIM 300215), Agenesis of the Corpus Callosum with Abnormal Genitalia (OMIM 30004), and Lissencephaly with cerebellar hypoplasia (19). ARX impacts interneuron generation, development and migration (40) and loss of ARX expression in interneurons alters their excitability and causes epilepsy in mice (33,39). In animal models it was shown that Arx acts with FoxA2 to regulate expression of Shh (36).…”

Section: Discussionmentioning

confidence: 99%

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Cortical interneuron development is affected in leukodystrophy 4H

Dooves

Kok

Holmes

et al. 2022

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4H leukodystrophy is a rare genetic disorder classically characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism. With the discovery that 4H is caused by mutations that affect RNA polymerase III, mainly involved in the transcription of small non-coding RNAs, also patients with atypical presentations with mainly a neuronal phenotype were identified. Pathomechanisms of 4H brain abnormalities are still unknown and research is hampered by a lack of preclinical models. We aimed to identify cells and pathways that are affected by 4H mutations using induced pluripotent stem cell models. RNA sequencing analysis on induced pluripotent stem cell-derived cerebellar cells revealed several differentially expressed genes between 4H patients and control samples, including reduced ARX expression. As ARX is involved in early brain and interneuron development, we studied and confirmed interneuron changes in primary tissue of 4H patients. Subsequently, we studied interneuron changes in more depth and analyzed induced pluripotent stem cell-derived cortical neuron cultures for changes in neuronal morphology, synaptic balance, network activity and myelination. We showed a decreased percentage of GABAergic synapses in 4H, which correlated to increased neuronal network activity. Treatment of cultures with GABA antagonists led to a significant increase in neuronal network activity in control cells but not in 4H cells, also pointing to lack of inhibitory activity in 4H. Myelination and oligodendrocyte maturation in cultures with 4H neurons was normal, and treatment with sonic hedgehog agonist SAG did not improve 4H related neuronal phenotypes. qPCR analysis revealed increased expression of parvalbumin interneuron marker ERBB4, suggesting that the development rather than generation of interneurons may be affected in 4H. Together, these results indicate that interneurons are involved, possibly parvalbumin interneurons, in disease mechanisms of 4H leukodystrophy.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Cortical interneuron development is affected in leukodystrophy 4H

Dooves

Kok

Holmes

et al. 2022

Preprint

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“…Here, we describe our protocol for the isolation of pure young adult PV interneurons and preparation of high-quality RNA from these cells. For complete details on the use and execution of this protocol, please refer to Joseph et al. (2021) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Joseph et al. (2021) .…”

mentioning

confidence: 99%

Protocol for isolating young adult parvalbumin interneurons from the mouse brain for extraction of high-quality RNA

et al. 2021

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Summary Dysfunction in the parvalbumin (PV) subclass of GABAergic interneurons is implicated in several neurodevelopmental disorders that evolve in severity with postnatal developmental stages. Understanding the molecular underpinnings of the postnatal changes in the function of PV interneurons has been limited by the difficulty in the isolation of pure adult PV interneurons and high-quality RNA. Here, we describe our protocol for the isolation of pure young adult PV interneurons and preparation of high-quality RNA from these cells. For complete details on the use and execution of this protocol, please refer to Joseph et al. (2021) .

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