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We previously reported that APP and its family members, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), regulate intrinsic neuronal excitability and synaptic plasticity in excitatory principal neurons, though APP family is dispensable for neuronal survival. However, the physiological role of APP family in inhibitory interneurons remains poorly understood. Here, we use our previously characterized floxed\n                    <jats:italic>APP<\/jats:italic>\n                    ,\n                    <jats:italic>APLP1<\/jats:italic>\n                    ,\n                    <jats:italic>APLP2<\/jats:italic>\n                    and\n                    <jats:italic>GAD2-Cre<\/jats:italic>\n                    alleles to generate inhibitory neuron-specific conditional triple knockout (IN-\n                    <jats:italic>APP\/APLP1\/APLP2<\/jats:italic>\n                    cTKO) mice. Our electrophysiological analysis of acute hippocampal slices revealed that IN-\n                    <jats:italic>APP\/APLP1\/APLP2<\/jats:italic>\n                    cTKO CA1 pyramidal neurons exhibit increased amplitudes of evoked GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor-mediated inhibitory postsynaptic currents (IPSCs), while basal spontaneous IPSC frequency and amplitude remain unchanged. At Schaffer collateral (SC)\u2013CA1 synapses, short-train frequency facilitation is enhanced in slices from IN-\n                    <jats:italic>APP\/APLP1\/APLP2<\/jats:italic>\n                    cTKO mice, whereas paired-pulse facilitation (PPF) and long-term potentiation (LTP) are normal. Consistent with a cell-autonomous interneuron defect, basal excitatory transmission, measured by spontaneous and miniature excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons, is unaltered. These data show that APP family in inhibitory interneurons regulates activity-dependent inhibitory output without overtly perturbing baseline glutamatergic transmission and thus, indirectly shapes short-term facilitation at SC\u2013CA1 synapses. Together with our earlier findings in excitatory neuron-specific\n                    <jats:italic>APP\/APLP1\/APLP2<\/jats:italic>\n                    cTKO mice showing intrinsic hyperexcitability, enhanced short-term facilitation, and impaired LTP, these results suggest that the APP family modulates inhibitory and excitatory functions at SC\u2013CA1 synapses through complementary mechanisms in principal neurons and interneurons.\n                  <\/jats:p>","DOI":"10.1186\/s13041-026-01296-0","type":"journal-article","created":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T05:07:08Z","timestamp":1774760828000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["APP family in inhibitory neurons controls inhibitory recruitment and short-term plasticity in the hippocampus"],"prefix":"10.1186","volume":"19","author":[{"given":"Sang Hun","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jongkyun","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vadim Y.","family":"Bolshakov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"issue":"44","key":"1296_CR1","doi-asserted-by":"publisher","first-page":"E9366","DOI":"10.1073\/pnas.1705841114","volume":"114","author":"R Rubin","year":"2017","unstructured":"Rubin R, Abbott LF, Sompolinsky H. 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