Dysfunction of Trio GEF1 involves in excitatory/inhibitory imbalance and autism-like behaviors through regulation of interneuron migration

Sun, Xiaoxuan; Wang, Lifang; Wei, Chengwen; Sun, Mengwen; Li, Qiongwei; Meng, Hu; Yue, Weihua; Zhang, Dai; Li, Jun

doi:10.1038/s41380-021-01109-x

Cited by 15 publications

(35 citation statements)

References 73 publications

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“…Consistent with the literature [ 33 , 34 ], a variety of cognitive, emotional, and social related behaviors of rodents may not be displayed sensitively. Therefore, we used a variety of behavioral tests to assess the effect of ASK1 cKO on the behavioral phenotypes.…”

Section: Resultssupporting

confidence: 80%

“…In our study, we used a variety of neurobehavioral that the results of animal behavioral experiments were not completely consistent, especially behavioral experiments that detected cognitive functions and emotions. For example, Sun X et al [33] claimed that the autismlike behaviors of Trio K1431M mutant mice were partially rescued by activation of GABA signaling, with decreased repetitive and stereotyped behaviors in marble burying test and increased time in center zone in open field test after GABA signaling activation. However, the time in open arms was not increased in elevated plus-maze test.…”

Section: Discussionmentioning

confidence: 99%

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Conditional knockout of ASK1 in microglia/macrophages attenuates epileptic seizures and long-term neurobehavioural comorbidities by modulating the inflammatory responses of microglia/macrophages

Zhang

Wang

et al. 2022

J Neuroinflammation

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Background Apoptosis signal-regulating kinase 1 (ASK1) not only causes neuronal programmed cell death via the mitochondrial pathway but also is an essential component of the signalling cascade during microglial activation. We hypothesize that ASK1 selective deletion modulates inflammatory responses in microglia/macrophages(Mi/Mϕ) and attenuates seizure severity and long-term cognitive impairments in an epileptic mouse model. Methods Mi/Mϕ-specific ASK1 conditional knockout (ASK1 cKO) mice were obtained for experiments by mating ASK1flox/flox mice with CX3CR1creER mice with tamoxifen induction. Epileptic seizures were induced by intrahippocampal injection of kainic acid (KA). ASK1 expression and distribution were detected by western blotting and immunofluorescence staining. Seizures were monitored for 24 h per day with video recordings. Cognition, social and stress related activities were assessed with the Y maze test and the three-chamber social novelty preference test. The heterogeneous Mi/Mϕ status and inflammatory profiles were assessed with immunofluorescence staining and real-time polymerase chain reaction (q-PCR). Immunofluorescence staining was used to detect the proportion of Mi/Mϕ in contact with apoptotic neurons, as well as neuronal damage. Results ASK1 was highly expressed in Mi/Mϕ during the acute phase of epilepsy. Conditional knockout of ASK1 in Mi/Mϕ markedly reduced the frequency of seizures in the acute phase and the frequency of spontaneous recurrent seizures (SRSs) in the chronic phase. In addition, ASK1 conditional knockout mice displayed long-term neurobehavioral improvements during the Y maze test and the three-chamber social novelty preference test. ASK1 selective knockout mitigated neuroinflammation, as evidenced by lower levels of Iba1+/CD16+ proinflammatory Mi/Mϕ. Conditional knockout of ASK1 increased Mi/Mϕ proportion in contact with apoptotic neurons. Neuronal loss was partially restored by ASK1 selective knockout. Conclusion Conditional knockout of ASK1 in Mi/Mϕ reduced seizure severity, neurobehavioral impairments, and histological damage, at least via inhibiting proinflammatory microglia/macrophages responses. ASK1 in microglia/macrophages is a potential therapeutic target for inflammatory responses in epilepsy.

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Section: Resultssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Conditional knockout of ASK1 in microglia/macrophages attenuates epileptic seizures and long-term neurobehavioural comorbidities by modulating the inflammatory responses of microglia/macrophages

Zhang

Wang

et al. 2022

J Neuroinflammation

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“…Our results suggest that the loss of Trio is particularly detrimental to the tangential migration of GABAergic INs, as also suggested by others 16 , and that its selective deletion in INs suffices to impair cortical inhibition and to induce epilepsy and ASD-like phenotypes in mice. This finding expands a growing body of evidence suggesting that a primary deficit of cortical inhibition, and particularly of PV-expressing INs (PV-INs), results in epilepsy and ASD-like behaviors in rodents [38][39][40][41][42] .…”

Section: Interneuronopathies In Nddssupporting

confidence: 87%

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.

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“…Recording hardware (Avisoft UltraSound Gate 116 Hm with a high-quality condenser microphone) and software (Avisoft SASLab Pro Recorder) were from Avisoft Bioacoustics (sampling frequency, 300 kHz; fast Fourier transform length, 1024 points; 16-bit format). Both male and female pups were used ( 57 ).…”

Section: Methodsmentioning

confidence: 99%

“…We recorded the sequence of arm entries every time. The percentage of accurate spontaneous alternations was calculated ( 57 ).…”

Section: Methodsmentioning

confidence: 99%

Auts2 deletion involves in DG hypoplasia and social recognition deficit: The developmental and neural circuit mechanisms

Sun

You

et al. 2022

Sci. Adv.

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The involvement of genetic risk and the underlying developmental and neural circuit mechanisms in autism-related social deficit are largely unclear. Here, we report that deletion of AUTS2 , a high-susceptibility gene of ASDs, caused postnatal dentate gyrus (DG) hypoplasia, which was closely relevant to social recognition deficit. Furthermore, a previously unknown mechanism for neural cell migration in postnatal DG development was identified, in which Auts2-related signaling played a vital role as the transcription repressor. Moreover, the supramammillary nucleus (SuM)–DG-CA3 neural circuit was found to be involved in social recognition and affected in Auts2 -deleted mice due to DG hypoplasia. Correction of DG-CA3 synaptic transmission by using a pharmacological approach or chemo/optogenetic activation of the SuM-DG circuit restored the social recognition deficit in Auts2 -deleted mice. Our findings demonstrated the vital role of Auts2 in postnatal DG development, and this role was critical for SuM-DG-CA3 neural circuit-mediated social recognition behavior.

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Dysfunction of Trio GEF1 involves in excitatory/inhibitory imbalance and autism-like behaviors through regulation of interneuron migration

Cited by 15 publications

References 73 publications

Conditional knockout of ASK1 in microglia/macrophages attenuates epileptic seizures and long-term neurobehavioural comorbidities by modulating the inflammatory responses of microglia/macrophages

Conditional knockout of ASK1 in microglia/macrophages attenuates epileptic seizures and long-term neurobehavioural comorbidities by modulating the inflammatory responses of microglia/macrophages

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

Auts2 deletion involves in DG hypoplasia and social recognition deficit: The developmental and neural circuit mechanisms

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