Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX)

Loring, Karagh E.; Mattiske, Tessa; Lee, Kristie; Zysk, Aneta; Jackson, Matilda R.; Noebels, Jeffrey L.; Shoubridge, Cheryl

doi:10.1016/j.nbd.2021.105329

Cited by 6 publications

(5 citation statements)

References 49 publications

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“…Interestingly, increases in mIPSC amplitude, but not sIPSC amplitude, was increased in APC cKO females compared to APC cKO males. This is consistent with sex-specific changes reported in other ISS models (Marsh et al, 2009; Ono et al, 2011; Briggs et al, 2014; Olivetti et al, 2014; Dube et al, 2015; Frost et al, 2015; Gataullina et al, 2016; Siehr et al, 2020; Akman et al, 2021; Loring et al, 2021) and indicates sex-specific changes should be investigated in future studies. No effects of sex on adult density of PV+INs, G42-GFP-INs, Lhx6-GFP+ INs, or SST+ INs, or any measures of inhibitory synaptic transmission were seen.…”

Section: Discussionsupporting

confidence: 90%

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Ryner

Derera

Armbruster

et al. 2022

Preprint

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Infantile Spasms syndrome (ISS) is a childhood epilepsy syndrome characterized by infantile or late onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IS are not well understood. Multiple human ISS risk genes are linked to Wnt/beta-catenin signaling, a pathway which controls developmental transcriptional programs and promotes glutamatergic excitation via beta-catenin's role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the beta-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIIalphaCre) in mice increased beta-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of inhibitory GABAergic interneurons (INs) is disrupted in APC cKOs. IN dysfunction is implicated in human ISS, is a feature of other rodent models of ISS and may contribute to the manifestation of spasms and seizures. We found that parvalbumin positive INs (PV+INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak time of behavioral spasms. PV+INs received excessive excitatory input and their intrinsic ability to fire action potentials was reduced at all timepoints examined (P9, P14, P60). Subsequently, synaptic inhibition of pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased inhibition at P14 and enhanced inhibition at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to ISS-related phenotypes.

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Section: Discussionsupporting

confidence: 90%

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Ryner

Derera

Armbruster

et al. 2022

Preprint

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“…They found that in early postnatal mice (a specific time window), estradiol can prevent spasms in infancy and seizures in adult by restoring the number of interneurons in the cortex and striatum 101 . A more recent study also confirmed that estradiol treatment reduces the number of seizures although it fails to affect other abnormal behavioral and cognitive outcomes 24 . Consistent with this, the cortical defects observed in mice have been associated with abnormal behavior in mice 22 .…”

Section: Discussionmentioning

confidence: 85%

“…Interestingly, mice lacking Arx in cortical projection neuron precursors did not develop seizures, despite being hyperactive and having behavioral abnormalities 22 . In contrast, mice with a PAE mutation knocked in showed fewer GABAergic interneurons in the cortex 17,23 and had seizures 24–27 . Although these mouse models have advanced our understanding the role ARX plays in several neurological conditions, they fail to fully recapitulate its complete role in human brain development as mice miss key aspects of human development.…”

Section: Introductionmentioning

confidence: 93%

Dual effects ofARXpoly-alanine mutations in human cortical and interneuron development

Nieto-Estevez,

Varma,

Mirsadeghi

et al. 2024

Preprint

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Mutations in ARX, an X-linked gene, are implicated in a wide spectrum of neurological disorders including patients who have intellectual disability and epilepsy. Mouse models have shown that Arx is critical for cortical development and interneuron migration, however they do not recapitulate the full phenotype observed in patients. Moreover, the epilepsy in many patients with poly-alanine tract expansion (PAE) mutations in ARX show pharmacoresistance, emphasizing the need to develop new treatments. Here, we used human neural organoid models to study the consequences of PAE mutations, one of the most prevalent mutations in ARX. We found that PAE mutations result in an early increase in radial glia cells and intermediate progenitor cells, and premature differentiation leading to a loss of cortical neurons at later timepoints. Moreover, ARX expression is upregulated in CO derived from patient at 30 DIV which alters the expression of CDKN1C, SFRP1, DLK1 and FABP7, among others. We also found a cell autonomously enhanced interneuron migration, which can be rescued by CXCR4 inhibition. Furthermore, ARXPAE assembloids had hyper-activity and synchrony evident from the early stages. These data provide novel insights to the pathogenesis of these and likely related human neurological disorders and identifies a critical window for therapeutic interventions.

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“…Late E2 administration (P33–P40) was ineffective in preventing seizures. E2 also reduced seizures in the two other mouse models of Arx mutations, PA1 and PA2 122 . An effect of E2 on spasms was not observed in the betamethasone‐NMDA 123 and the triple hit model of IESS 124 .…”

Section: Estrogen Effectsmentioning

confidence: 89%

“…E2 also reduced seizures in the two other mouse models of Arx mutations, PA1 and PA2. 122 An effect of E2 on spasms was not observed in the betamethasone-NMDA 123 and the triple hit model of IESS. 124 It is thus possible that E2 is effective in preventing spasms when there are deficits in certain GABAergic interneuron subpopulations, such as those found in Arx mutations in rodents and humans.…”

Section: Estrogen Effectsmentioning

confidence: 96%

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

Ng,

Choudhary,

Barrett

et al. 2023

Epilepsia

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The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age‐dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug‐resistant IESS.

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Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX)

Cited by 6 publications

References 49 publications

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Dual effects ofARXpoly-alanine mutations in human cortical and interneuron development

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

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