<i>Nf1</i>deletion results in depletion of the<i>Lhx6</i>transcription factor and a specific loss of parvalbumin+ cortical interneurons

Angara, Kartik; Pai, Emily Ling-Lin; Bilinovich, Stephanie M.; Stafford, April M; Nguyen, Julie T.; Paul, Anirban; Rubenstein, John L.R.; Vogt, Daniel

doi:10.1101/746214

Cited by 6 publications

(15 citation statements)

References 63 publications

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“…While the transcriptional mechanisms of CIN development have been intensely studied, the signaling pathways that serve as intermediaries between extracellular stimulation and gene expression changes are relatively less clear. Recent work has shown that hyperactive MEK-ERK1/2 and PI3K-linked signaling pathways have critical roles in CIN development and subtype specification (Angara et al, 2020; Malik et al, 2019; Vogt et al, 2015). However, the field still lacks crucial information on whether activation of ERK1/2 signaling is necessary for CIN subtype identity.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

Knowles

Holter

et al. 2022

Preprint

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The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we show that CIN-autonomous ERK1/2 signaling is necessary for chemogenetic activity-dependent FOSB expression in vivo. This deficit coincides with a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of ERK1/2 deleted inhibitory neurons. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.

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Section: Introductionmentioning

confidence: 99%

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

Knowles

Holter

et al. 2022

Preprint

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“…One possible explanation for the different situation in nf1 +/mice could be that the development of inhibitory innervation in BDNF transgenic mice (Huang et al, 1999b) and benzodiazepine-treated mice (Iwai et al, 2003) was also advanced, while this was not the case in nf1 +/mice. A recent study in mice in which nf1 was inactivated in precursors of cortical interneurons (Angara et al, 2020) showed evidence that nf1 deletion could even delay PV+ interneuron development. Fewer perineuronal nets were found in somatosensory cortex of these mice.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Critical Period Plasticity in a Mouse Model of Neurofibromatosis Type 1

et al. 2020

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Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter γ-amino butyric acid (GABA). Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and wildtype litter mates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development. Significance: Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that in a mouse model of Neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of Neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in Neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials.

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“…We performed MGE primary cultures as described in Angara et al ( 2020 ). Briefly, we cultured MGE cells in DMEM supplemented with 10% FBS and penicillin/streptomycin from time of seeding until 1 day in vitro .…”

Section: Methodsmentioning

confidence: 99%

“…CIN dysfunction is implicated in ASD and altered in both humans diagnosed with ASD and in ASD genetic deletion models (Vogt et al, 2015a , 2018 ; Hoffman et al, 2016 ; Hashemi et al, 2017 ; Jung et al, 2017 ; Soghomonian et al, 2017 ; Pla et al, 2018 ; Elbert et al, 2019 ; Malik et al, 2019 ; Angara et al, 2020 ). CINs are derived from the medial and caudal ganglionic eminences (MGE and CGE), as well as the preoptic area (Wonders and Anderson, 2006 ; Gelman et al, 2011 ; Hu et al, 2017b ).…”

Section: Introductionmentioning

confidence: 99%

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

Wundrach

Martinetti

Stafford

et al. 2020

Front. Mol. Neurosci.

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The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants' neurological impact better.

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Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+ cortical interneurons

Cited by 6 publications

References 63 publications

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

Disruption of Critical Period Plasticity in a Mouse Model of Neurofibromatosis Type 1

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

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