Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model / Najwa OUALI ALAMI ; Oumayma AOUSJI ; Esther POGATZKI-ZAHN ; Peter K. ZAHN ; Hanna WILHELM ; Dhruva DESHPANDE ; Elmira KHATAMSAZ ; Alberto CATANESE ; Sarah WOELFLE ; Michael SCHÖN ; Sanjay JAIN ; Stefanie GRABRUCKER ; Albert C. LUDOLPH ; Chiara VERPELLI ; Jens MICHAELIS ; Tobias M. BOECKERS ; Francesco ROSELLI in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 21 p. Titre : Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model Type de document : Texte imprimé et/ou numérique Auteurs : Najwa OUALI ALAMI, Auteur ; Oumayma AOUSJI, Auteur ; Esther POGATZKI-ZAHN, Auteur ; Peter K. ZAHN, Auteur ; Hanna WILHELM, Auteur ; Dhruva DESHPANDE, Auteur ; Elmira KHATAMSAZ, Auteur ; Alberto CATANESE, Auteur ; Sarah WOELFLE, Auteur ; Michael SCHÖN, Auteur ; Sanjay JAIN, Auteur ; Stefanie GRABRUCKER, Auteur ; Albert C. LUDOLPH, Auteur ; Chiara VERPELLI, Auteur ; Jens MICHAELIS, Auteur ; Tobias M. BOECKERS, Auteur ; Francesco ROSELLI, Auteur Article en page(s) : 21 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. METHODS: We have used a Shank2(-/-) mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. RESULTS: We determined that Shank2(-/-) mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2(-/-) mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2(-/-) mice. LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. CONCLUSION: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. En ligne : http://dx.doi.org/10.1186/s13229-023-00552-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513 [article] Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model [Texte imprimé et/ou numérique] / Najwa OUALI ALAMI, Auteur ; Oumayma AOUSJI, Auteur ; Esther POGATZKI-ZAHN, Auteur ; Peter K. ZAHN, Auteur ; Hanna WILHELM, Auteur ; Dhruva DESHPANDE, Auteur ; Elmira KHATAMSAZ, Auteur ; Alberto CATANESE, Auteur ; Sarah WOELFLE, Auteur ; Michael SCHÖN, Auteur ; Sanjay JAIN, Auteur ; Stefanie GRABRUCKER, Auteur ; Albert C. LUDOLPH, Auteur ; Chiara VERPELLI, Auteur ; Jens MICHAELIS, Auteur ; Tobias M. BOECKERS, Auteur ; Francesco ROSELLI, Auteur . - 21 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 21 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. METHODS: We have used a Shank2(-/-) mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. RESULTS: We determined that Shank2(-/-) mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2(-/-) mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2(-/-) mice. LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. CONCLUSION: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. En ligne : http://dx.doi.org/10.1186/s13229-023-00552-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513

Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling / Silvia LANDI ; Alessia STEFANONI ; Gabriele NARDI ; Marica ALBANESI ; Helen F. BAUER ; Enrico PRACUCCI ; Michael SCHÖN ; Gian Michele RATTO ; Tobias M. BOECKERS ; Carlo SALA ; Chiara VERPELLI in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 28 p. Titre : Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling Type de document : Texte imprimé et/ou numérique Auteurs : Silvia LANDI, Auteur ; Alessia STEFANONI, Auteur ; Gabriele NARDI, Auteur ; Marica ALBANESI, Auteur ; Helen F. BAUER, Auteur ; Enrico PRACUCCI, Auteur ; Michael SCHÖN, Auteur ; Gian Michele RATTO, Auteur ; Tobias M. BOECKERS, Auteur ; Carlo SALA, Auteur ; Chiara VERPELLI, Auteur Article en page(s) : 28 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions. METHODS: We recorded local field potentials and visual evoked responses in the visual cortex of Shank3?11(-/-) mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre(+/-) Shank3(Fl/Wt) conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration. RESULTS: We found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABA(A) receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre(+/-) Shank3(Fl/Wt) compared with Pv-cre(+/-) Shank3(Wt/Wt) mice. These deficits were rescued with ganaxolone, a positive modulator of GABA(A) receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice. LIMITATIONS: Despite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects. CONCLUSIONS: Our study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral deficits in Shank3 KO mice. Overall, our study highlights the importance of investigating the role of inhibitory neurons and potential therapeutic interventions in neurodevelopmental disorders such as PMS. En ligne : http://dx.doi.org/10.1186/s13229-023-00557-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513 [article] Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling [Texte imprimé et/ou numérique] / Silvia LANDI, Auteur ; Alessia STEFANONI, Auteur ; Gabriele NARDI, Auteur ; Marica ALBANESI, Auteur ; Helen F. BAUER, Auteur ; Enrico PRACUCCI, Auteur ; Michael SCHÖN, Auteur ; Gian Michele RATTO, Auteur ; Tobias M. BOECKERS, Auteur ; Carlo SALA, Auteur ; Chiara VERPELLI, Auteur . - 28 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 28 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions. METHODS: We recorded local field potentials and visual evoked responses in the visual cortex of Shank3?11(-/-) mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre(+/-) Shank3(Fl/Wt) conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration. RESULTS: We found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABA(A) receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre(+/-) Shank3(Fl/Wt) compared with Pv-cre(+/-) Shank3(Wt/Wt) mice. These deficits were rescued with ganaxolone, a positive modulator of GABA(A) receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice. LIMITATIONS: Despite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects. CONCLUSIONS: Our study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral deficits in Shank3 KO mice. Overall, our study highlights the importance of investigating the role of inhibitory neurons and potential therapeutic interventions in neurodevelopmental disorders such as PMS. En ligne : http://dx.doi.org/10.1186/s13229-023-00557-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=513

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