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By RNAseq analysis of the transcriptomic changes in the brain of NEGR1\u2010deficient mice, we found that NEGR1 deficiency affects the expression of the\n                    <jats:italic>Gad2<\/jats:italic>\n                    gene. We show that glutamic acid decarboxylase 65 (GAD65), the\n                    <jats:italic>Gad2<\/jats:italic>\n                    \u2010 encoded enzyme synthesizing the inhibitory neurotransmitter GABA on synaptic vesicles, accumulates non\u2010synaptically in brains of NEGR1\u2010deficient mice. The density of non\u2010synaptic GAD65 accumulations is also increased in NEGR1 deficient cultured hypothalamic neurons, and this effect is rescued by re\u2010expression of NEGR1. By using a novel biosensor of the plasma membrane attachment of GAD65, we demonstrate that GAD65 attaches to the plasma membrane. NEGR1 promotes palmitoylation\u2010dependent clearance of GAD65 from the plasma membrane and targeting of GAD65 to plasma membrane\u2010derived endocytic vesicles. In NEGR1 deficient cultured hypothalamic neurons, the synaptic and extrasynaptic levels of the plasma membrane attached GAD65 are increased, and the synaptic levels of GABA are reduced. NEGR1\u2010deficient mice are characterized by reduced body weight, lower GABAergic synapse densities in the arcuate nucleus, and blunted responsiveness to the reinforcing effects of food rewards. Our results indicate that abnormalities in synaptic GABA synthesis can contribute to brain disorders associated with abnormal expression of NEGR1 in humans.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16279-fig-0010-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16279","type":"journal-article","created":{"date-parts":[[2024,12,15]],"date-time":"2024-12-15T22:33:57Z","timestamp":1734302037000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Neuronal growth regulator 1 (\n                    <scp>NEGR1<\/scp>\n                    ) promotes the synaptic targeting of glutamic acid decarboxylase 65 (\n                    <scp>GAD65<\/scp>\n                    )"],"prefix":"10.1111","volume":"169","author":[{"given":"Feifei","family":"Su","sequence":"first","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Pfundstein","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saroj","family":"Sah","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Keable","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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