Early rescue of interneuron disease trajectory in developmental epilepsies

Siehr, Meagan S; Noebels, Jeffrey L.

doi:10.1016/j.conb.2015.10.007

Cited by 5 publications

(4 citation statements)

References 60 publications

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“…Importantly, we demonstrate that while each GEF domain individually contributes to fundamental aspects of IN migration, with critical contributions from the GEFD2-RhoA pathway, their synergistic effects are required to ensure proper IN migration. These findings support an emergent literature suggesting that a subset of genetically determined DEE/ASD/NDD result from a primary impairment of IN migration (see reviews 38, 106, 107 , and that such disorders may ultimately benefit from pharmacological or cell-based therapies aiming to reestablish circuit inhibition 108–111 .…”

Section: Discussionsupporting

confidence: 81%

“…It also binds microtubule plus ends of growing microtubules during neurite extension 105 . Thus, altered microtubule dynamics likely also contributes to some aspects 38,106,107 , and that such disorders may ultimately benefit from pharmacological or cell-based therapies aiming to reestablish circuit inhibition [108][109][110][111] .…”

Section: Trio Controls Cytoskeletal Actin Remodeling During the Tange...mentioning

confidence: 99%

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Both GEF domains of the autism and epilepsy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Eid

Lokmane

Raju

et al. 2023

Preprint

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Recessive mutations in theTRIOgene are associated with intellectual deficiency (ID), autism spectrum disorder (ASD) and developmental epileptic encephalopathies (DEE). TRIO is a dual guanine nucleotide exchange factor (GEF) that activates Rac1, Cdc42 and RhoA. Trio has been extensively studied in excitatory neurons, and has recently been found to regulate the switch from tangential to radial migration in GABAergic interneurons (INs), through GEFD1-Rac1-dependent SDF1α/CXCR4 signalling. Given the central role of Rho-GTPases during neuronal migration and the implication of IN pathologies in ASD and DEE, we investigated the relative roles of both Trio's GEF domains in regulating the dynamics of INs tangential migration. In Trio-/-mice, we observed reduced numbers of tangentially migrating INs, with intact progenitor proliferation. Further, we noted increased growth cone collapse in developing INs, suggesting altered cytoskeleton dynamics. To bypass the embryonic mortality of Trio-/-mice, we generatedDlx5/6Cre;Trioc/cconditional mutant mice, which develop spontaneous seizures and behavioral deficits reminiscent of ASD and ID. These phenotypes are associated with reduced cortical IN density and functional cortical inhibition. Mechanistically, this reduction of cortical IN numbers reflects a premature switch to radial migration, with an aberrant early entry in the cortical plate, as well as major deficits in cytoskeletal dynamics, including enhanced leading neurite branching and slower nucleokinesis reflecting reduced actin filament condensation and turnover. Further, we show that both Trio GEFD1 and GEFD2 domains are required for proper IN migration, with a dominant role of the RhoA-activating GEFD2 domain. Altogether, our data show a critical role of the DEE/ASD-associated Trio gene in the establishment of cortical inhibition and the requirement of both GEF domains in regulating IN migration dynamics.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Trio Controls Cytoskeletal Actin Remodeling During the Tange...mentioning

confidence: 99%

Both GEF domains of the autism and epilepsy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Eid

Lokmane

Raju

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Importantly, we demonstrate that while each GEF domain individually contributes to fundamental aspects of IN migration, with critical contributions from the GEFD2-RhoA pathway, their synergistic effects are required to ensure proper IN migration. These ndings support an emergent literature suggesting that a subset of genetically determined DEE/ASD/NDD result from a primary impairment of IN migration (see reviews 38,106,107 , and that such disorders may ultimately bene t from pharmacological or cell-based therapies aiming to reestablish circuit inhibition [108][109][110][111] . Cre recombination) and Dlx5/6 Cre littermates (i.e.…”

Section: Trio Controls Cytoskeletal Actin Remodeling During the Tange...supporting

confidence: 72%

Both GEF domains of the autism and epilepsy-associated Trio protein are required for proper tangential migration of GABAergic interneurons

Rossignol

Eid

Raju

et al. 2023

Preprint

View full text Add to dashboard Cite

Recessive mutations in the TRIO gene are associated with intellectual deficiency (ID), autism spectrum disorder (ASD) and developmental epileptic encephalopathies (DEE). TRIO is a dual guanine nucleotide exchange factor (GEF) that activates Rac1, Cdc42 and RhoA. Trio has been extensively studied in excitatory neurons, and has recently been found to regulate the switch from tangential to radial migration in GABAergic interneurons (INs), through GEFD1-Rac1-dependent SDF1α/CXCR4 signalling. Given the central role of Rho-GTPases during neuronal migration and the implication of IN pathologies in ASD and DEE, we investigated the relative roles of both Trio’s GEF domains in regulating the dynamics of INs tangential migration. In Trio−/− mice, we observed reduced numbers of tangentially migrating INs, with intact progenitor proliferation. Further, we noted increased growth cone collapse in developing INs, suggesting altered cytoskeleton dynamics. To bypass the embryonic mortality of Trio−/− mice, we generated Dlx5/6Cre;Trioc/c conditional mutant mice, which develop spontaneous seizures and behavioral deficits reminiscent of ASD and ID. These phenotypes are associated with reduced cortical IN density and functional cortical inhibition. Mechanistically, this reduction of cortical IN numbers reflects a premature switch to radial migration, with an aberrant early entry in the cortical plate, as well as major deficits in cytoskeletal dynamics, including enhanced leading neurite branching and slower nucleokinesis reflecting reduced actin filament condensation and turnover. Further, we show that both Trio GEFD1 and GEFD2 domains are required for proper IN migration, with a dominant role of the RhoA-activating GEFD2 domain. Altogether, our data show a critical role of the DEE/ASD-associated Trio gene in the establishment of cortical inhibition and the requirement of both GEF domains in regulating IN migration dynamics.

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“…Despite different genetic origins and involvement in distinct signaling pathways, 30% of these disease-linked genes are predicted to impact inhibitory interneuron function (Siehr and Noebels, 2016). In this issue of Neuron, Vuong et al (2018) add to the richness of cell-specific mechanisms essential for maintaining cortical excitatory/inhibitory balance.…”

Section: Protected By a Foxmentioning

confidence: 99%