Reelin cells and sex‐dependent synaptopathology in autism following postnatal immune activation

Ardalan, Maryam; Chumak, Tetyana; Quist, Alexandra; Hermans, Eva; Rafati, Ali; Gravina, Giacomo; Shiadeh, Seyedeh Marzieh Jabbari; Svedin, Pernilla; Alabaf, Setareh; Hansen, Brian; Wegener, Gregers; Westberg, Lars; Mallard, Carina

doi:10.1111/bph.15859

Cited by 15 publications

(7 citation statements)

References 113 publications

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“…A patient with p.Arg846His mutation of L1, which is close to the position mutated in the L1/858-863 mice, displayed childhood onset hyperactivity, psychosis and autism spectrum disorder with symptoms overlapping with those seen in obsessive-compulsive disorders [74]. Interestingly, in mice treated with lipopolysaccharide, social withdrawal and increased stereotype activity in males was linked to a reduced number and volume of Reelin expressing cells, to a reduced expression of trans-synaptic cell-adhesion molecules and to alterations in spine density [76]. Although only male L1/858-863 mice exhibited increased digging activity which could suggest sex-dependent enhanced activity or increased stereotype behavior, male and female mutant mice did not show sex-dependent alterations in brain morphology or differences in numbers of principle cells in the hippocampus.…”

Section: Discussionmentioning

confidence: 96%

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

et al. 2023

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Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma in adulthood. Mutations of L1 in humans result in L1 syndrome, which is associated with mild-to-severe brain malformations and mental disabilities. Furthermore, mutations in the extracellular domain were shown to cause a severe phenotype more often than mutations in the intracellular domain. To explore the outcome of a mutation in the extracellular domain, we generated mice with disruption of the dibasic sequences RK and KR that localize to position 858RKHSKR863 in the third fibronectin type III domain of murine L1. These mice exhibit alterations in exploratory behavior and enhanced marble burying activity. Mutant mice display higher numbers of caspase 3-positive neurons, a reduced number of principle neurons in the hippocampus, and an enhanced number of glial cells. Experiments suggest that disruption of the dibasic sequence in L1 results in subtle impairments in brain structure and functions leading to obsessive-like behavior in males and reduced anxiety in females.

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Section: Discussionmentioning

confidence: 96%

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

et al. 2023

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“…Diffusion timings were δ/Δ = 7/16 ms, and remaining parameters were 10 avs, TE=39.2 ms, TR = 4000 ms, BW= 277 kHz, 80 axial slices. DKI analysis has been described previously 31, 32 . Briefly, data was Rician noise floor adjusted, denoised and corrected for Gibbs-ringing before fitting to the DKI signal equation (Matlab, The Mathworks, USA).…”

Section: Methodsmentioning

confidence: 99%

STING activation counters glioblastoma by vascular alteration and immune surveillance

Joseph,

Blaavand,

Cai

et al. 2023

Preprint

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Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.

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“…The counting frame size was 854.33 µm 2 . The number density of cells was calculated by applying the following formula ( Ardalan et al, 2022 ): where N v indicates the number of cells per volume of sampling brain region, Σ Q - is the number of cells counted, and V is the volume of sampled regions of interest.…”

Section: Methodsmentioning

confidence: 99%

“…The counting frame size was 854.33 µm 2 . The number density of cells was calculated by applying the following formula (Ardalan et al, 2022):…”

Section: Analysis Of Hmgb1-positive Cell Number Density In the Hippoc...mentioning

confidence: 99%

Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic–Ischemic Brain Injury in Neonatal Mice

Kawamura,

Singh Mallah,

Ardalan

et al. 2023

ASN Neuro

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A clinical challenge remains in the treatment of hypoxic–ischemic brain injury in newborns. Nicotinamide adenine dinucleotide (NAD+) has beneficial effects in animal models of adult stroke. Here, we aimed to understand the short- and long-term neuroprotective effects of NAD+-promoting substance nicotinamide mononucleotide (NMN) in a well-established brain injury model in neonatal mice. Postnatal day (PND) 9 male and female mice were subjected to cerebral hypoxia–ischemia and treated with saline or NMN (50 mg/kg) immediately after hypoxia–ischemia. At different time points after hypoxia–ischemia, hippocampal NAD+, caspase-3 activity, protein expression of SIRT1, SIRT6, release of high mobility group box-1 (HMGB1), long-term neuropathological outcome, short-term developmental behavior, and long-term motor and memory function were evaluated. Neonatal hypoxia–ischemia reduced NAD+ and SIRT6 levels, but not SIRT1, in the injured hippocampus, while HMGB1 release was significantly increased. NMN treatment normalized hippocampal NAD+ and SIRT6 levels, while caspase-3 activity and HMGB1 release were significantly reduced. NMN alleviated tissue loss in the long-term and improved early developmental behavior, as well as motor and memory function. This study shows that NMN treatment provides neuroprotection in a clinically relevant neonatal animal model of hypoxia–ischemia in mice suggesting as a possible novel treatment for neonatal brain injury. Summary Statement Neonatal hypoxia–ischemia reduces nicotinamide adenine dinucleotide (NAD+) and SIRT6 levels in the injured hippocampus. Hippocampal high mobility group box-1 (HMGB1) release is significantly increased after neonatal hypoxia–ischemia. Nicotinamide mononucleotide (NMN) treatment normalizes hippocampal NAD+ and SIRT6 levels, with significant decrease in caspase-3 activity and HMGB1 release. NMN improves early developmental behavior, as well as motor and memory function.

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Reelin cells and sex‐dependent synaptopathology in autism following postnatal immune activation

Cited by 15 publications

References 113 publications

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

STING activation counters glioblastoma by vascular alteration and immune surveillance

Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic–Ischemic Brain Injury in Neonatal Mice

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