Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex
SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction, and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical...
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eLife Sciences Publications Ltd
2025-08-01
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| Online Access: | https://elifesciences.org/articles/97100 |
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| author | Ruggiero Francavilla Bidisha Chattopadhyaya Jorelle Linda Damo Kamda Vidya Jadhav Said Kourrich Jacques L Michaud Graziella Di Cristo |
| author_facet | Ruggiero Francavilla Bidisha Chattopadhyaya Jorelle Linda Damo Kamda Vidya Jadhav Said Kourrich Jacques L Michaud Graziella Di Cristo |
| author_sort | Ruggiero Francavilla |
| collection | DOAJ |
| description | SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction, and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development, recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, are unknown. Here, we examined whether, and how, embryonic-onset Syngap1 haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found that Syngap1 haploinsufficiency significantly affected the intrinsic properties, overall leading to increased firing threshold and decreased excitatory synaptic drive in Parvalbumin (PV)+ neurons in adult layer IV A1. Further, the AMPA component of thalamocortical evoked EPSC was decreased in PV+ cells from mutant mice. Mutant somatostatin (SST)+ interneurons exhibited decreased spontaneous excitatory input and impaired evoked firing without alterations in firing threshold. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest that Syngap1 plays a specific role in the maturation of PV+ cell-intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients. |
| format | Article |
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| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-732d787920a54b2eb27c08d4d0dcebf32025-08-20T04:01:01ZengeLife Sciences Publications LtdeLife2050-084X2025-08-011310.7554/eLife.97100Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortexRuggiero Francavilla0https://orcid.org/0009-0004-0192-6646Bidisha Chattopadhyaya1Jorelle Linda Damo Kamda2https://orcid.org/0000-0001-7140-4334Vidya Jadhav3Said Kourrich4Jacques L Michaud5Graziella Di Cristo6https://orcid.org/0000-0003-4464-4994CHU Sainte-Justine Azrieli Research Centre, Montreal, Canada; Department of Neurosciences, Université de Montréal, Montréal, CanadaCHU Sainte-Justine Azrieli Research Centre, Montreal, CanadaCHU Sainte-Justine Azrieli Research Centre, Montreal, Canada; Department of Neurosciences, Université de Montréal, Montréal, CanadaCHU Sainte-Justine Azrieli Research Centre, Montreal, Canada; Department of Neurosciences, Université de Montréal, Montréal, CanadaDépartement des sciences biologiques, UQAM, Montreal, Canada; Centre d’Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois, Pavillon des Sciences biologiques, Montréal, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, CanadaCHU Sainte-Justine Azrieli Research Centre, Montreal, Canada; Department of Neurosciences, Université de Montréal, Montréal, Canada; Department of Pediatrics, Université de Montréal, Montreal, CanadaCHU Sainte-Justine Azrieli Research Centre, Montreal, Canada; Department of Neurosciences, Université de Montréal, Montréal, CanadaSYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction, and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development, recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, are unknown. Here, we examined whether, and how, embryonic-onset Syngap1 haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found that Syngap1 haploinsufficiency significantly affected the intrinsic properties, overall leading to increased firing threshold and decreased excitatory synaptic drive in Parvalbumin (PV)+ neurons in adult layer IV A1. Further, the AMPA component of thalamocortical evoked EPSC was decreased in PV+ cells from mutant mice. Mutant somatostatin (SST)+ interneurons exhibited decreased spontaneous excitatory input and impaired evoked firing without alterations in firing threshold. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest that Syngap1 plays a specific role in the maturation of PV+ cell-intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.https://elifesciences.org/articles/97100intrinsic propertiescortical GABAergic interneuronsglutamatergic synapsesauditory cortexSyngap1 |
| spellingShingle | Ruggiero Francavilla Bidisha Chattopadhyaya Jorelle Linda Damo Kamda Vidya Jadhav Said Kourrich Jacques L Michaud Graziella Di Cristo Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex eLife intrinsic properties cortical GABAergic interneurons glutamatergic synapses auditory cortex Syngap1 |
| title | Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex |
| title_full | Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex |
| title_fullStr | Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex |
| title_full_unstemmed | Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex |
| title_short | Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex |
| title_sort | syngap1 regulates the synaptic drive and membrane excitability of parvalbumin positive interneurons in mouse auditory cortex |
| topic | intrinsic properties cortical GABAergic interneurons glutamatergic synapses auditory cortex Syngap1 |
| url | https://elifesciences.org/articles/97100 |
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