Publications by authors named "Ciprian M Bosoi"

6 Publications

  • Page 1 of 1

Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced seizures.

Neurobiol Dis 2021 12 4;161:105546. Epub 2021 Nov 4.

Centre de Recherche, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Département de Pédiatrie, Université de Montréal, Québec, Canada; Département de Neurosciences, Université de Montréal, Québec, Canada; Neurosurgery Service, Department of Surgery, Université de Montréal, Québec, Canada.

Febrile seizures (FS) are common, affecting 2-5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.
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http://dx.doi.org/10.1016/j.nbd.2021.105546DOI Listing
December 2021

Humanized mouse model of Rasmussen's encephalitis supports the immune-mediated hypothesis.

J Clin Invest 2018 05 9;128(5):2000-2009. Epub 2018 Apr 9.

Department of Microbiology, Infectious Diseases, and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ- and granzyme B-expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.
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http://dx.doi.org/10.1172/JCI97098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919802PMC
May 2018

Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model.

Epilepsy Behav 2018 02 26;79:117-125. Epub 2017 Dec 26.

Centre de Recherche, Centre Hospitalier Universitaire CHU-Sainte-Justine, Québec, Canada; Département de Neurosciences, Faculté de Médecine, Université de Montréal, Québec, Canada. Electronic address:

Levetiracetam (LEV), and its newer selective analog brivaracetam (BRV), are two seizure medications that share an innovative mechanism of action targeting the Synaptic Vesicle Protein 2A (SV2A), altering neurotransmitter release and decreasing seizure frequency. Behavioral changes are the most significant adverse effects reported by patients taking LEV. We hypothesize that BRV, the more potent SV2A analog, could exert less behavioral side effects, as it requires lower doses than LEV. Using Kainic Acid (KA)-treated and control rats, we measured adverse behavioral effect profiles of LEV, BRV, or Saline, on social and nonsocial behaviors. Our data indicate that both tested drugs had no effect on locomotion, anxiety levels, fear learning, depression-like behavior, and memory retention in rats. However, when considering social interactions, we first confirmed the epilepsy-induced strong increase in aggressive behaviors and specific hippocampal neuronal loss. We furthermore observed, in Sham rats, that LEV-treated animals were 2 times faster to attack at first encounter, had 5 times more aggressive behaviors, and had significantly less social behaviors than control rats. In all circumstances, BRV rats behaved like Saline rats, suggesting that BRV treatment in rats leads to significantly less aggressive behaviors than LEV treatment at the doses used, while there are limited differential effects between these two drugs on other types of behaviors. Since increased aggressiveness has been reported in patients well controlled on LEV, this study indicates based on our findings, that BRV could represent an effective alternative to LEV to limit aggressiveness problems due to this antiepileptic drug (AED) therapy.
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http://dx.doi.org/10.1016/j.yebeh.2017.11.019DOI Listing
February 2018

Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.

Hum Mutat 2011 Dec 23;32(12):1371-5. Epub 2011 Sep 23.

Department of Obstetrics and Gynecology, CHU Sainte Justine Research Center and University of Montreal, Montreal, Canada.

The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure, and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations.
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http://dx.doi.org/10.1002/humu.21589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217084PMC
December 2011

A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene.

Dev Dyn 2011 Apr 18;240(4):839-49. Epub 2011 Feb 18.

Department of Obstetrics and Gynecology, CHU Sainte Justine Research Center and University of Montreal, Montreal, Canada.

Vangl2 forms part of the planar cell polarity signalling pathway and is the gene defective in the Looptail (Lp) mouse mutant. Two previously described alleles, Lp and Lp(m1Jus) , segregate in a semi-dominant fashion, with heterozygotes displaying the looped-tail appearance, while homozygotes show the neural tube defect called craniorachischisis. Here, we report a novel experimentally induced allele, Lp(m2Jus) , that carries a missense mutation, R259L, in Vangl2. This mutation was specific to the Lp phenotype and absent from both parental strains and 28 other inbred strains. Notably, this mutation segregates in a recessive manner with all heterozygotes appearing normal and 47% of homozygotes showing a looped-tail. Homozygous Lp(m2Jus) embryos showed spina bifida in 12%. Lp(m2Jus) genetically interacts with Lp with 77% of compound heterozygotes displaying craniorachischisis. Vangl2(R259L) behaved like the wild-type allele in overexpression and morpholino knockdown/rescue assays in zebrafish embryos. These data suggest that Lp(m2Jus) represents a new hypomorphic allele of Lp.
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http://dx.doi.org/10.1002/dvdy.22577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593115PMC
April 2011

Novel mutations in VANGL1 in neural tube defects.

Hum Mutat 2009 Jul;30(7):E706-15

CHU Sainte Justine Research Center, Department of Obstetrics and Gynecology, University of Montreal, Montreal, QC, Canada. [email protected] recherche-ste-justine.qc.ca

Neural tube defects (NTDs) are severe congenital malformations caused by failure of the neural tube to close during neurulation. Their etiology is complex involving both environmental and genetic factors. We have recently reported three mutations in the planar cell polarity gene VANGL1 associated with NTDs. The aim of the present study was to define the role of VANGL1 genetic variants in the development of NTDs in a large cohort of various ethnic origins. We identified five novel missense variants in VANGL1, p.Ser83Leu, p.Phe153Ser, p.Arg181Gln, p.Leu202Phe and p.Ala404Ser, occurring in sporadic and familial cases of spinal dysraphisms. All five variants affect evolutionary conserved residues and are absent from all controls analyzed. This study provides further evidence supporting the role of VANGL1 as a risk factor in the development of spinal NTDs.
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http://dx.doi.org/10.1002/humu.21026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885434PMC
July 2009
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