Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome / Antonis ASIMINAS in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 49 p. Titre : Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Antonis ASIMINAS, Auteur ; Sam A. BOOKER, Auteur ; Owen R. DANDO, Auteur ; Zrinko KOZIC, Auteur ; Daisy ARKELL, Auteur ; Felicity H. INKPEN, Auteur ; Anna SUMERA, Auteur ; Irem AKYEL, Auteur ; Peter C. KIND, Auteur ; Emma R. WOOD, Auteur Article en page(s) : 49 p. Langues : Anglais (eng) Mots-clés : Mice  Rats  Animals  Fragile X Syndrome/genetics  Intellectual Disability  Autism Spectrum Disorder  Mice, Knockout  Hippocampus/metabolism  Fragile X Mental Retardation Protein/genetics  Disease Models, Animal Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(-/y)). METHODS: We recorded from the CA1 in Fmr1(-/y) and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(-/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(-/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(-/y) rats. These findings were consistent with increased excitability of Fmr1(-/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(-/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(-/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(-/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00528-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome [Texte imprimé et/ou numérique] / Antonis ASIMINAS, Auteur ; Sam A. BOOKER, Auteur ; Owen R. DANDO, Auteur ; Zrinko KOZIC, Auteur ; Daisy ARKELL, Auteur ; Felicity H. INKPEN, Auteur ; Anna SUMERA, Auteur ; Irem AKYEL, Auteur ; Peter C. KIND, Auteur ; Emma R. WOOD, Auteur . - 49 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 49 p. Mots-clés : Mice  Rats  Animals  Fragile X Syndrome/genetics  Intellectual Disability  Autism Spectrum Disorder  Mice, Knockout  Hippocampus/metabolism  Fragile X Mental Retardation Protein/genetics  Disease Models, Animal Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(-/y)). METHODS: We recorded from the CA1 in Fmr1(-/y) and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(-/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(-/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(-/y) rats. These findings were consistent with increased excitability of Fmr1(-/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(-/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(-/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(-/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00528-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism / Natasha J. ANSTEY in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 34 p. Titre : Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism Type de document : Texte imprimé et/ou numérique Auteurs : Natasha J. ANSTEY, Auteur ; Vijayakumar KAPGAL, Auteur ; Shashank TIWARI, Auteur ; Thomas C. WATSON, Auteur ; Anna K. H. TOFT, Auteur ; Owen R. DANDO, Auteur ; Felicity H. INKPEN, Auteur ; Paul S. BAXTER, Auteur ; Zrinko KOZIĆ, Auteur ; Adam D. JACKSON, Auteur ; Xin HE, Auteur ; Mohammad SARFARAZ NAWAZ, Auteur ; Aiman KAYENAAT, Auteur ; Aditi BHATTACHARYA, Auteur ; David J. A. WYLLIE, Auteur ; Sumantra CHATTARJI, Auteur ; Emma R. WOOD, Auteur ; Oliver HARDT, Auteur ; Peter C. KIND, Auteur Article en page(s) : 34 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/metabolism  Fear/physiology  Freezing  Humans  Neurons/physiology  Periaqueductal Gray/metabolism  Rats  Autism  Fear  Flight  Intellectual disability  Neuroligin-3  Periaqueductal grey Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3(-/y) rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3(-/y) rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3(-/y) rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3(-/y) rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3(-/y) than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3(-/y) rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00511-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism [Texte imprimé et/ou numérique] / Natasha J. ANSTEY, Auteur ; Vijayakumar KAPGAL, Auteur ; Shashank TIWARI, Auteur ; Thomas C. WATSON, Auteur ; Anna K. H. TOFT, Auteur ; Owen R. DANDO, Auteur ; Felicity H. INKPEN, Auteur ; Paul S. BAXTER, Auteur ; Zrinko KOZIĆ, Auteur ; Adam D. JACKSON, Auteur ; Xin HE, Auteur ; Mohammad SARFARAZ NAWAZ, Auteur ; Aiman KAYENAAT, Auteur ; Aditi BHATTACHARYA, Auteur ; David J. A. WYLLIE, Auteur ; Sumantra CHATTARJI, Auteur ; Emma R. WOOD, Auteur ; Oliver HARDT, Auteur ; Peter C. KIND, Auteur . - 34 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 34 p. Mots-clés : Animals  Autistic Disorder/metabolism  Fear/physiology  Freezing  Humans  Neurons/physiology  Periaqueductal Gray/metabolism  Rats  Autism  Fear  Flight  Intellectual disability  Neuroligin-3  Periaqueductal grey Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3(-/y) rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3(-/y) rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3(-/y) rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3(-/y) rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3(-/y) than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3(-/y) rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00511-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

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