{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/700"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/700","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation","abstract":"The mammalian brain contains a disproportionately large percentage of the body's cholesterol, steady-state levels of which are maintained within a narrow range to preserve membrane function. The brain is denied access to circulating lipoproteins by the blood-brain barrier and therefore relies on de novo cholesterol synthesis through the mevalonate pathway to meet the tissue's requirement for this essential lipid. A small amount of brain cholesterol is turned over daily in select neurons by cholesterol 24-hydroxylase, which catalyzes the production of the membrane-permeable oxysterol 24(S)-hydroxycholesterol and represents the major pathway of cholesterol catabolism in this organ. Mice lacking 24-hydroxylase have a decreased rate of brain cholesterol synthesis and exhibit deficiencies in spatial, associative, and motor learning. Hippocampal slices prepared from these mice are unable to support the induction of long-term potentiation, a type of synaptic strengthening thought to underlie learning and memory. The ability of 24-hydroxylase knockout slices to exhibit long-term potentiation can be restored by treatment with geranylgeraniol, an isoprenoid end-product of the mevalonate pathway. Mechanistic insight into the role of geranylgeraniol in long-term potentiation has been revealed by calcium imaging studies in neurons cultured from wild-type and 24-hydroxylase knockout embryos. Neurons from mice lacking 24-hydroxylase have specific defects in N-methyl-D-aspartate (NMDA) receptor function, a subtype of ionotropic glutamate receptor essential for long-term potentiation. The subunit composition of NMDA receptors located in various functional pools is normal in 24-hydroxylase knockout hippocampus, suggesting that geranylgeraniol does not affect expression of NMDA receptors. Localization studies of 24-hydroxylase show the enzyme is predominantly expressed in the endoplasmic reticulum throughout the soma and dendrites of selected hippocampal, cerebellar, and cortical neurons, consistent with a postsynaptic need for cholesterol turnover in neurons of brain regions important for learning and memory. These findings reveal that cholesterol turnover is important to produce a constant supply of geranylgeraniol, which in turn is necessary for the induction of long-term potentiation and presumably learning in mice.","abstract_html":"The mammalian brain contains a disproportionately large percentage of the body's cholesterol, steady-state levels of which are maintained within a narrow range to preserve membrane function. The brain is denied access to circulating lipoproteins by the blood-brain barrier and therefore relies on de novo cholesterol synthesis through the mevalonate pathway to meet the tissue's requirement for this essential lipid. A small amount of brain cholesterol is turned over daily in select neurons by cholesterol 24-hydroxylase, which catalyzes the production of the membrane-permeable oxysterol 24(S)-hydroxycholesterol and represents the major pathway of cholesterol catabolism in this organ. Mice lacking 24-hydroxylase have a decreased rate of brain cholesterol synthesis and exhibit deficiencies in spatial, associative, and motor learning. Hippocampal slices prepared from these mice are unable to support the induction of long-term potentiation, a type of synaptic strengthening thought to underlie learning and memory. The ability of 24-hydroxylase knockout slices to exhibit long-term potentiation can be restored by treatment with geranylgeraniol, an isoprenoid end-product of the mevalonate pathway. Mechanistic insight into the role of geranylgeraniol in long-term potentiation has been revealed by calcium imaging studies in neurons cultured from wild-type and 24-hydroxylase knockout embryos. Neurons from mice lacking 24-hydroxylase have specific defects in N-methyl-D-aspartate (NMDA) receptor function, a subtype of ionotropic glutamate receptor essential for long-term potentiation. The subunit composition of NMDA receptors located in various functional pools is normal in 24-hydroxylase knockout hippocampus, suggesting that geranylgeraniol does not affect expression of NMDA receptors. Localization studies of 24-hydroxylase show the enzyme is predominantly expressed in the endoplasmic reticulum throughout the soma and dendrites of selected hippocampal, cerebellar, and cortical neurons, consistent with a postsynaptic need for cholesterol turnover in neurons of brain regions important for learning and memory. These findings reveal that cholesterol turnover is important to produce a constant supply of geranylgeraniol, which in turn is necessary for the induction of long-term potentiation and presumably learning in mice.","abstract_has_math":false,"creators":["Ramirez, Denise Marie O'Donnell"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Russell, David W."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07-12T18:52:29Z","date_published":"2010-07-12T18:52:29Z","updated_at":"2026-07-24T05:52:08Z","subjects":["Steroid Hydroxylases","Cholesterol","Brain"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["754645059"],"render_values":[{"text":"754645059","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/700","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Russell, David W."]},{"key":"dc:creator","label":"Author","values":["Ramirez, Denise Marie O'Donnell"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T18:52:29Z","2009-06-18"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Steroid Hydroxylases","Cholesterol","Brain"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/700","754645059"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The mammalian brain contains a disproportionately large percentage of the body's cholesterol, steady-state levels of which are maintained within a narrow range to preserve membrane function. The brain is denied access to circulating lipoproteins by the blood-brain barrier and therefore relies on de novo cholesterol synthesis through the mevalonate pathway to meet the tissue's requirement for this essential lipid. A small amount of brain cholesterol is turned over daily in select neurons by cholesterol 24-hydroxylase, which catalyzes the production of the membrane-permeable oxysterol 24(S)-hydroxycholesterol and represents the major pathway of cholesterol catabolism in this organ. Mice lacking 24-hydroxylase have a decreased rate of brain cholesterol synthesis and exhibit deficiencies in spatial, associative, and motor learning. Hippocampal slices prepared from these mice are unable to support the induction of long-term potentiation, a type of synaptic strengthening thought to underlie learning and memory. The ability of 24-hydroxylase knockout slices to exhibit long-term potentiation can be restored by treatment with geranylgeraniol, an isoprenoid end-product of the mevalonate pathway. Mechanistic insight into the role of geranylgeraniol in long-term potentiation has been revealed by calcium imaging studies in neurons cultured from wild-type and 24-hydroxylase knockout embryos. Neurons from mice lacking 24-hydroxylase have specific defects in N-methyl-D-aspartate (NMDA) receptor function, a subtype of ionotropic glutamate receptor essential for long-term potentiation. The subunit composition of NMDA receptors located in various functional pools is normal in 24-hydroxylase knockout hippocampus, suggesting that geranylgeraniol does not affect expression of NMDA receptors. Localization studies of 24-hydroxylase show the enzyme is predominantly expressed in the endoplasmic reticulum throughout the soma and dendrites of selected hippocampal, cerebellar, and cortical neurons, consistent with a postsynaptic need for cholesterol turnover in neurons of brain regions important for learning and memory. These findings reveal that cholesterol turnover is important to produce a constant supply of geranylgeraniol, which in turn is necessary for the induction of long-term potentiation and presumably learning in mice."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation"]}]}],"canonical_facts":{"dc:contributor":["Russell, David W."],"dc:creator":["Ramirez, Denise Marie O'Donnell"],"dc:date":["2010-07-12T18:52:29Z","2009-06-18"],"dc:description":["The mammalian brain contains a disproportionately large percentage of the body's cholesterol, steady-state levels of which are maintained within a narrow range to preserve membrane function. The brain is denied access to circulating lipoproteins by the blood-brain barrier and therefore relies on de novo cholesterol synthesis through the mevalonate pathway to meet the tissue's requirement for this essential lipid. A small amount of brain cholesterol is turned over daily in select neurons by cholesterol 24-hydroxylase, which catalyzes the production of the membrane-permeable oxysterol 24(S)-hydroxycholesterol and represents the major pathway of cholesterol catabolism in this organ. Mice lacking 24-hydroxylase have a decreased rate of brain cholesterol synthesis and exhibit deficiencies in spatial, associative, and motor learning. Hippocampal slices prepared from these mice are unable to support the induction of long-term potentiation, a type of synaptic strengthening thought to underlie learning and memory. The ability of 24-hydroxylase knockout slices to exhibit long-term potentiation can be restored by treatment with geranylgeraniol, an isoprenoid end-product of the mevalonate pathway. Mechanistic insight into the role of geranylgeraniol in long-term potentiation has been revealed by calcium imaging studies in neurons cultured from wild-type and 24-hydroxylase knockout embryos. Neurons from mice lacking 24-hydroxylase have specific defects in N-methyl-D-aspartate (NMDA) receptor function, a subtype of ionotropic glutamate receptor essential for long-term potentiation. The subunit composition of NMDA receptors located in various functional pools is normal in 24-hydroxylase knockout hippocampus, suggesting that geranylgeraniol does not affect expression of NMDA receptors. Localization studies of 24-hydroxylase show the enzyme is predominantly expressed in the endoplasmic reticulum throughout the soma and dendrites of selected hippocampal, cerebellar, and cortical neurons, consistent with a postsynaptic need for cholesterol turnover in neurons of brain regions important for learning and memory. These findings reveal that cholesterol turnover is important to produce a constant supply of geranylgeraniol, which in turn is necessary for the induction of long-term potentiation and presumably learning in mice."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/700","754645059"],"dc:language":["en"],"dc:subject":["Steroid Hydroxylases","Cholesterol","Brain"],"dc:title":["Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:08Z"}