{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:38:54Z","timestamp":1785425934595,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of China","doi-asserted-by":"publisher","award":["2021ZD0202300"],"award-info":[{"award-number":["2021ZD0202300"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2021ZD0202300"],"award-info":[{"award-number":["2021ZD0202300"]}],"id":[{"id":"https:\/\/ror.org\/027s68j25","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundations of China","doi-asserted-by":"publisher","award":["32171005"],"award-info":[{"award-number":["32171005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32171005"],"award-info":[{"award-number":["32171005"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cerebellar climbing fiber\u2013Purkinje cell (CF\u2013PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF\u2013PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF\u2013PC LTD in cerebellar slices from dopamine \u03b2-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF\u2013PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF\u2013PC LTD accompanied by an increased N2\/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF\u2013PC LTD following blockade of \u03b12-AR or \u03b12A-AR, but not \u03b12B-AR or \u03b12C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of \u03b12-AR or \u03b12A-AR, but not \u03b12B-AR or \u03b12C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF\u2013PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust \u03b12A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF\u2013PC LTD by triggering Glu-LTD at CF terminals through the \u03b12A-AR\/CDK5\/PKA signaling cascade in the mouse cerebellar cortex.<\/jats:p>","DOI":"10.3390\/biom16071042","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"1042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemogenetic Activation of LC Noradrenergic Afferents Facilitates Cerebellar CF\u2013PC LTD via Presynaptic \u03b12A\u2013AR\/CDK5\/PKA Signaling"],"prefix":"10.3390","volume":"16","author":[{"given":"Xu-Dong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji 133002, China"},{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"},{"name":"Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Han","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji 133002, China"},{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"},{"name":"Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang-Tong","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang-Yue","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yi","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6921-5028","authenticated-orcid":false,"given":"Chun-Ping","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji 133002, China"},{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"},{"name":"Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Lai","family":"Qiu","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, Jilin Medical University, Jilin City 132013, China"},{"name":"Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin City 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5990","DOI":"10.1523\/JNEUROSCI.0038-06.2006","article-title":"Role of the Olivo-Cerebellar System in Timing","volume":"26","author":"Xu","year":"2006","journal-title":"J. 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