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TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional <jats:italic>Tsc1<\/jats:italic> haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We investigated the consequences of conditional heterozygous knockout of <jats:italic>Tsc1<\/jats:italic> in MGE-derived inhibitory cells by crossing <jats:italic>Nkx2.1<\/jats:italic><jats:sup>Cre\/wt<\/jats:sup>;<jats:italic>Tsc1<\/jats:italic><jats:sup>f\/f<\/jats:sup> mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, <jats:italic>Nkx2.1<\/jats:italic><jats:sup>Cre\/wt<\/jats:sup>;<jats:italic>Tsc1<\/jats:italic><jats:sup>f\/wt<\/jats:sup> mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of <jats:italic>Nkx2.1<\/jats:italic><jats:sup>Cre\/wt<\/jats:sup>;<jats:italic>Tsc1<\/jats:italic><jats:sup>f\/wt<\/jats:sup> mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of <jats:italic>Nkx2.1<\/jats:italic><jats:sup>Cre\/wt<\/jats:sup>;<jats:italic>Tsc1<\/jats:italic><jats:sup>f\/wt<\/jats:sup> mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results indicate that <jats:italic>Tsc1<\/jats:italic> haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the <jats:italic>Tsc1<\/jats:italic> mouse model of TSC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13229-020-00340-7","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T11:03:42Z","timestamp":1588763022000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-3593","authenticated-orcid":false,"given":"Nabila","family":"Haji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Riebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2272-1138","authenticated-orcid":false,"given":"Argel","family":"Aguilar-Valles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-9209","authenticated-orcid":false,"given":"Julien","family":"Artinian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7707-943X","authenticated-orcid":false,"given":"Isabel","family":"Laplante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4056-0574","authenticated-orcid":false,"given":"Jean-Claude","family":"Lacaille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,6]]},"reference":[{"issue":"7","key":"340_CR1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.2174\/138920208786241243","volume":"9","author":"V Napolioni","year":"2008","unstructured":"Napolioni V, Curatolo P. 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