IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex

Mehta, Anuradha; Shirai, Yoshinori; Kouyama-Suzuki, Emi; Zhou, Mengyun; Yoshizawa, Takahiro; Yanagawa, Toru; Mori, Tomohisa; Tabuchi, Katsuhiko

doi:10.3390/cells10102724

Cited by 13 publications

(7 citation statements)

References 43 publications

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“…IQSEC2 is a protein abundantly localized to the postsynaptic density of the excitatory synapse and plays an important role in neuronal development and synaptic plasticity ( 123 ). IQSEC2 knockout has been reported to impair synaptic function in the medial prefrontal cortex, which is responsible for social deficits in mice ( 124 ). Given the MFs of these proteins, our results suggest their down-regulation, as downstream of Ca 2+ dysregulation by RyR2 channels, might contribute to cognitive dysfunction in cancer mice treated with DOX.…”

Section: Discussionmentioning

confidence: 99%

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Liu,

Reiken,

Dridi

et al. 2023

Sci. Transl. Med.

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Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca 2+ ) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca 2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor–α and transforming growth factor–β signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure–associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca 2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies.

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Section: Discussionmentioning

confidence: 99%

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Liu,

Reiken,

Dridi

et al. 2023

Sci. Transl. Med.

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“…pFSy-ratSyn-Flag-CASK (WT): Total rat brain RNA extraction was described elsewhere [ 32 ]. In short, the total RNA of the rat forebrain (Wistar, 6-week-old male) was isolated by ISOGEN (Takara, Shiga, Japan) and cDNAs were obtained using SuperScript II reverse transcriptase (Invitrogen, Waltham, MA, USA) and Oligo(dT) primer following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome

Guo

Kouyama-Suzuki

Shirai

et al. 2023

Cells

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Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome.

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“…Histological analysis was followed by the previous procedures [ 43 , 44 , 45 ]. Briefly, under deep anesthesia, the mice were perfused transcardially with ice-cold phosphate-buffered saline (PBS, pH 7.4), followed by 4% paraformaldehyde in PBS.…”

Section: Methodsmentioning

confidence: 99%

An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice

Pang

Mori

Badawi

et al. 2022

IJMS

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Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment.

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IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex

Cited by 13 publications

References 43 publications

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome

An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice

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