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Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology.\n                    <jats:italic>CDKL5<\/jats:italic>\n                    encodes a serine-threonine kinase with significant homology to GSK3\u03b2, which has also been linked to synaptic function. Further,\n                    <jats:italic>Cdkl5<\/jats:italic>\n                    knock-out rodents have increased GSK3\u03b2 activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3\u03b2 activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3\u03b2. These compounds are very soluble in water but blood\u2013brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.\n                  <\/jats:p>","DOI":"10.7554\/elife.88206","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:15:13Z","timestamp":1690272913000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88206","source":"Crossref","is-referenced-by-count":13,"title":["Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology"],"prefix":"10.7554","volume":"12","author":[{"given":"Anna","family":"Castano","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wmf1y16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, University of Colorado School of Medicine","place":["Aurora, United 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