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Syngap1 disruption induced by recombination between inverted loxP sites is associated with hippocampal interneuron dysfunction.

Abdessattar KhlaifiaVidya JadhavMarc DanikThéo BadraMartin BerryerAlexandre Dionne-LaporteBidisha ChattopadhyayaGraziella Di CristoJean-Claude LacailleJacques L Michaud
Published in: eNeuro (2023)
SYNGAP1 haploinsufficiency in humans causes intellectual disability. SYNGAP1 is highly expressed in cortical excitatory neurons and, reducing its expression in mice accelerates the maturation of excitatory synapses during sensitive developmental periods, restricts the critical period window for plasticity, and impairs cognition. However, its specific role in interneurons remains largely undetermined.In this study, we investigated the effects of conditional Syngap1 disruption in medial ganglionic eminence (MGE)-derived interneurons on hippocampal interneuron firing properties and excitatory synaptic inputs, as well as on pyramidal cell synaptic inhibition and synaptic integration.We show that conditional Syngap1 disruption in MGE-derived interneurons results in cell-specific impairment of firing properties of hippocampal Nkx2.1 fast-spiking interneurons, with enhancement of their AMPAR-mediated excitatory synaptic inputs but compromised short-term plasticity. In contrast, regular-spiking Nkx2.1 interneurons are largely unaffected. These changes are associated with impaired pyramidal cell synaptic inhibition and enhanced summation of excitatory responses. Unexpectedly, we found that the Syngap1 flox allele used in this study contains inverted loxP sites and that its targeted recombination in MGE-derived interneurons induces some cell loss during embryonic development and the reversible inversion of the sequence flanked by the loxP sites in post-mitotic cells.Together, these results suggest that Syngap1 plays a role in cell-specific regulation of hippocampal interneuron function and inhibition of pyramidal cells in mice. However, because of our finding that the Syngap1 flox allele used in this study contains inverted loxP sites, it will be important to further investigate interneuron function using a different Syngap1 conditional allele. Significance Statement Previous studies have shown that the intellectual disability gene SYNGAP1 is expressed in parvalbumin GABAergic interneurons but its role in these cells remains poorly understood. Here, we found that Syngap1 disruption in Medial Ganglionic Eminence (MGE)-derived cells selectively affected hippocampal Nkx2.1 fast-spiking interneurons firing properties, their excitatory inputs strength and short-term plasticity, without affecting Nkx2.1 regular-spiking interneurons. These changes were associated with reduced synaptic inhibition of pyramidal cells. Unexpectedly, we found that the Syngap1 flox allele used in this study contains inverted loxP sites and that its recombination induces cell loss during development and the inversion of the Syngap1 targeted sequence in post-mitotic cells. Thus, it will be important to further study interneuron function using a different Syngap1 conditional allele.
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