60 recherche sur le mot-clé 'Disease Models, Animal'

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder / Carol L. MURRAY ; John KEALY ; Clodagh TOWNS ; Andrew ROCHE ; Arshed NAZMI ; Michelle DORAN ; John P. LOWRY ; Colm CUNNINGHAM in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 43 p. Titre : Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder Type de document : texte imprimé Auteurs : Carol L. MURRAY, Auteur ; John KEALY, Auteur ; Clodagh TOWNS, Auteur ; Andrew ROCHE, Auteur ; Arshed NAZMI, Auteur ; Michelle DORAN, Auteur ; John P. LOWRY, Auteur ; Colm CUNNINGHAM, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Humans  Mice  Animals  *Autism Spectrum Disorder/therapy  Lipopolysaccharides/toxicity  Temperature  Disease Models, Animal  Mice, Inbred Strains  Brain  *Hyperthermia, Induced/methods Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 ug/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p<0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits. En ligne : https://dx.doi.org/10.1186/s13229-023-00569-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518 [article] Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder [texte imprimé] / Carol L. MURRAY, Auteur ; John KEALY, Auteur ; Clodagh TOWNS, Auteur ; Andrew ROCHE, Auteur ; Arshed NAZMI, Auteur ; Michelle DORAN, Auteur ; John P. LOWRY, Auteur ; Colm CUNNINGHAM, Auteur . - 43 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 43 p. Mots-clés : Humans  Mice  Animals  *Autism Spectrum Disorder/therapy  Lipopolysaccharides/toxicity  Temperature  Disease Models, Animal  Mice, Inbred Strains  Brain  *Hyperthermia, Induced/methods Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 ug/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p<0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits. En ligne : https://dx.doi.org/10.1186/s13229-023-00569-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518

Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB / Katherine B. MCCULLOUGH in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB Type de document : texte imprimé Auteurs : Katherine B. MCCULLOUGH, Auteur ; Amanda TITUS, Auteur ; Kate REARDON, Auteur ; Sara CONYERS, Auteur ; Joseph D. DOUGHERTY, Auteur ; Xia GE, Auteur ; Joel R. GARBOW, Auteur ; Patricia DICKSON, Auteur ; Carla M. YUEDE, Auteur ; Susan E. MALONEY, Auteur Langues : Anglais (eng) Mots-clés : Humans  Animals  Adult  Child  Mucopolysaccharidosis III/genetics/pathology  Diffusion Tensor Imaging  Brain  Disease Models, Animal  Treatment Outcome  Aggression  Dominance  Fear conditioning  Gait  Lysosomal storage disorder  Mri/dti  Mucopolysaccharidosis IIIB  Sanfilippo B  Startle response  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. En ligne : https://dx.doi.org/10.1186/s11689-024-09534-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB [texte imprimé] / Katherine B. MCCULLOUGH, Auteur ; Amanda TITUS, Auteur ; Kate REARDON, Auteur ; Sara CONYERS, Auteur ; Joseph D. DOUGHERTY, Auteur ; Xia GE, Auteur ; Joel R. GARBOW, Auteur ; Patricia DICKSON, Auteur ; Carla M. YUEDE, Auteur ; Susan E. MALONEY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Animals  Adult  Child  Mucopolysaccharidosis III/genetics/pathology  Diffusion Tensor Imaging  Brain  Disease Models, Animal  Treatment Outcome  Aggression  Dominance  Fear conditioning  Gait  Lysosomal storage disorder  Mri/dti  Mucopolysaccharidosis IIIB  Sanfilippo B  Startle response  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. En ligne : https://dx.doi.org/10.1186/s11689-024-09534-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease / Yanya DING in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease Type de document : texte imprimé Auteurs : Yanya DING, Auteur ; Jingyu FENG, Auteur ; Viollandi PRIFTI, Auteur ; Grace A. RICO, Auteur ; Alexander G. SOLORZANO, Auteur ; Hayley E. CHANG, Auteur ; Edward G. FREEDMAN, Auteur ; John J. FOXE, Auteur ; Kuan Hong WANG, Auteur Langues : Anglais (eng) Mots-clés : Animals  Neuronal Ceroid-Lipofuscinoses/physiopathology/genetics  Disease Models, Animal  Female  Mice  Male  Disease Progression  Mice, Knockout  Membrane Glycoproteins/genetics  Molecular Chaperones/genetics  Evoked Potentials, Auditory, Brain Stem/physiology  Electroencephalography  Age Factors  Sex Characteristics  Sex Factors  Auditory brainstem response (ABR)  Auditory evoked potential (AEP)  Duration mismatch negativity (MMN)  Eeg  Translational biomarker  conducted in accordance with ethical standards for the care and use of animals of  the University Committee on Animal Resource (UCAR) at the University of Rochester  Medical Center (URMC, NY). Consent for publication: All authors are consent for  publication. Competing interests: The authors declare no competing financial  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. METHODS: Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout (Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. RESULTS: Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. CONCLUSIONS: These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease. En ligne : https://dx.doi.org/10.1186/s11689-025-09652-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease [texte imprimé] / Yanya DING, Auteur ; Jingyu FENG, Auteur ; Viollandi PRIFTI, Auteur ; Grace A. RICO, Auteur ; Alexander G. SOLORZANO, Auteur ; Hayley E. CHANG, Auteur ; Edward G. FREEDMAN, Auteur ; John J. FOXE, Auteur ; Kuan Hong WANG, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Neuronal Ceroid-Lipofuscinoses/physiopathology/genetics  Disease Models, Animal  Female  Mice  Male  Disease Progression  Mice, Knockout  Membrane Glycoproteins/genetics  Molecular Chaperones/genetics  Evoked Potentials, Auditory, Brain Stem/physiology  Electroencephalography  Age Factors  Sex Characteristics  Sex Factors  Auditory brainstem response (ABR)  Auditory evoked potential (AEP)  Duration mismatch negativity (MMN)  Eeg  Translational biomarker  conducted in accordance with ethical standards for the care and use of animals of  the University Committee on Animal Resource (UCAR) at the University of Rochester  Medical Center (URMC, NY). Consent for publication: All authors are consent for  publication. Competing interests: The authors declare no competing financial  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. METHODS: Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout (Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. RESULTS: Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. CONCLUSIONS: These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease. En ligne : https://dx.doi.org/10.1186/s11689-025-09652-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury / Panagiotis KRATIMENOS in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury Type de document : texte imprimé Auteurs : Panagiotis KRATIMENOS, Auteur ; Abhya VIJ, Auteur ; Robinson VIDVA, Auteur ; Ioannis KOUTROULIS, Auteur ; Maria DELIVORIA-PAPADOPOULOS, Auteur ; Vittorio GALLO, Auteur ; Aaron SATHYANESAN, Auteur Langues : Anglais (eng) Mots-clés : Animals  Animals, Newborn  Brain Injuries/metabolism  Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism  Cerebral Cortex/metabolism  Disease Models, Animal  Humans  Neurons/metabolism  Swine  Calcium/calmodulin  Computational modeling  Excitotoxicity  Neonatal brain injury  Nuclear calcium  SimBiology  Src kinase Index. décimale : PER Périodiques Résumé : BACKGROUND: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca(2+)-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca(2+)/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca(2+)-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. METHODS: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca(2+)-influx, and Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca(2+)/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. RESULTS: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca(2+) level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca(2+)-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca(2+)-influx and Bax expression to similar levels as pre-treatment. CONCLUSIONS: Our model identifies new dynamics of critical components in the Ca(2+)/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities. En ligne : https://dx.doi.org/10.1186/s11689-022-09431-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury [texte imprimé] / Panagiotis KRATIMENOS, Auteur ; Abhya VIJ, Auteur ; Robinson VIDVA, Auteur ; Ioannis KOUTROULIS, Auteur ; Maria DELIVORIA-PAPADOPOULOS, Auteur ; Vittorio GALLO, Auteur ; Aaron SATHYANESAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Animals  Animals, Newborn  Brain Injuries/metabolism  Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism  Cerebral Cortex/metabolism  Disease Models, Animal  Humans  Neurons/metabolism  Swine  Calcium/calmodulin  Computational modeling  Excitotoxicity  Neonatal brain injury  Nuclear calcium  SimBiology  Src kinase Index. décimale : PER Périodiques Résumé : BACKGROUND: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca(2+)-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca(2+)/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca(2+)-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. METHODS: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca(2+)-influx, and Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca(2+)/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. RESULTS: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca(2+) level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca(2+)-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca(2+)-influx and Bax expression to similar levels as pre-treatment. CONCLUSIONS: Our model identifies new dynamics of critical components in the Ca(2+)/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities. En ligne : https://dx.doi.org/10.1186/s11689-022-09431-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder / Mohammed Sarfaraz NAWAZ ; Peter C. KIND ; Michael A. COUSIN in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 26 Titre : Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder Type de document : texte imprimé Auteurs : Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur Article en page(s) : 26 Langues : Anglais (eng) Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder [texte imprimé] / Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur . - 26. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 26 Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models / Ugne KLIBAITE in Molecular Autism, 13 (2022)  

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Distinct early development trajectories in Nf1(±) and Tsc2(±) mouse models of autism / Helena FERREIRA in Journal of Neurodevelopmental Disorders, 17 (2025)  

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RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer's disease, and normative aging / Helen WONG in Journal of Neurodevelopmental Disorders, 14 (2022)  

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Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs / Feipeng ZHU in Molecular Autism, 15 (2024)  

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Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome / Rui-Ni WU in Journal of Neurodevelopmental Disorders, 12 (2020)  

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