Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age‐related cognitive phenotype
Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been tho...
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| creator | Tropea, Maria Rosaria Melone, Marcello Li Puma, Domenica Donatella Vacanti, Valeria Aceto, Giuseppe Bandiera, Bruno Trovato, Roberta Carmela Torrisi, Sebastiano Alfio Leggio, Gian Marco Palmeri, Agostino D'Ascenzo, Marcello Conti, Fiorenzo Grassi, Claudio Puzzo, Daniela |
| description | Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline.
Dopamine D3 receptors (D3Rs) blockade acts through the cAMP/PKA pathway leading to long‐lasting LTP and memory. D3Rs are mainly located in post‐synaptic dendrites and their blockade enhances basal synaptic transmission, AMPAR‐mediated currents, mEPSC amplitude, and the expression of PSD‐95, pGluA1, pCREB. In aged mice, D3R blockade reversed synaptic transmission and plasticity, post‐synaptic protein expression, and PSD length. Aged D3‐KO mice did not exhibit synaptic and memory deficits. |
| doi_str_mv | 10.1111/acel.14291 |
| format | Article |
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Dopamine D3 receptors (D3Rs) blockade acts through the cAMP/PKA pathway leading to long‐lasting LTP and memory. D3Rs are mainly located in post‐synaptic dendrites and their blockade enhances basal synaptic transmission, AMPAR‐mediated currents, mEPSC amplitude, and the expression of PSD‐95, pGluA1, pCREB. In aged mice, D3R blockade reversed synaptic transmission and plasticity, post‐synaptic protein expression, and PSD length. Aged D3‐KO mice did not exhibit synaptic and memory deficits.</description><identifier>ISSN: 1474-9718</identifier><identifier>ISSN: 1474-9726</identifier><identifier>EISSN: 1474-9726</identifier><identifier>DOI: 10.1111/acel.14291</identifier><identifier>PMID: 39236310</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Age ; aging ; Aging - metabolism ; Aging - physiology ; Animal cognition ; Animals ; Antibodies ; Brain ; Camps ; Cognition - physiology ; Cognitive ability ; Cyclic AMP response element-binding protein ; Dendrites ; Dopamine ; Dopamine D3 receptors ; Drug dosages ; Electron microscopy ; Experiments ; Hippocampus ; Hippocampus - metabolism ; Kinases ; Long-Term Potentiation ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy ; Phenotype ; Phenotypes ; Phosphatase ; Presynapse ; Protein kinase A ; Proteins ; Receptor mechanisms ; Receptors, Dopamine D3 - genetics ; Receptors, Dopamine D3 - metabolism ; Synapses - metabolism ; synaptic plasticity ; Synaptic Transmission ; Therapeutic targets ; Variance analysis ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><ispartof>Aging cell, 2024-11, Vol.23 (11), p.e14291-n/a</ispartof><rights>2024 The Author(s). published by Anatomical Society and John Wiley & Sons Ltd.</rights><rights>2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.</rights><rights>2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3381-1415be0dbb3bfb7d8bef4e763bd69e1c227a7f1c6c1a13057f9428078875c61d3</cites><orcidid>0000-0002-9542-2251</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561665/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561665/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39236310$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tropea, Maria Rosaria</creatorcontrib><creatorcontrib>Melone, Marcello</creatorcontrib><creatorcontrib>Li Puma, Domenica Donatella</creatorcontrib><creatorcontrib>Vacanti, Valeria</creatorcontrib><creatorcontrib>Aceto, Giuseppe</creatorcontrib><creatorcontrib>Bandiera, Bruno</creatorcontrib><creatorcontrib>Trovato, Roberta Carmela</creatorcontrib><creatorcontrib>Torrisi, Sebastiano Alfio</creatorcontrib><creatorcontrib>Leggio, Gian Marco</creatorcontrib><creatorcontrib>Palmeri, Agostino</creatorcontrib><creatorcontrib>D'Ascenzo, Marcello</creatorcontrib><creatorcontrib>Conti, Fiorenzo</creatorcontrib><creatorcontrib>Grassi, Claudio</creatorcontrib><creatorcontrib>Puzzo, Daniela</creatorcontrib><title>Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age‐related cognitive phenotype</title><title>Aging cell</title><addtitle>Aging Cell</addtitle><description>Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline.
Dopamine D3 receptors (D3Rs) blockade acts through the cAMP/PKA pathway leading to long‐lasting LTP and memory. D3Rs are mainly located in post‐synaptic dendrites and their blockade enhances basal synaptic transmission, AMPAR‐mediated currents, mEPSC amplitude, and the expression of PSD‐95, pGluA1, pCREB. In aged mice, D3R blockade reversed synaptic transmission and plasticity, post‐synaptic protein expression, and PSD length. Aged D3‐KO mice did not exhibit synaptic and memory deficits.</description><subject>Age</subject><subject>aging</subject><subject>Aging - metabolism</subject><subject>Aging - physiology</subject><subject>Animal cognition</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Brain</subject><subject>Camps</subject><subject>Cognition - physiology</subject><subject>Cognitive ability</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Dendrites</subject><subject>Dopamine</subject><subject>Dopamine D3 receptors</subject><subject>Drug dosages</subject><subject>Electron microscopy</subject><subject>Experiments</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Kinases</subject><subject>Long-Term Potentiation</subject><subject>Male</subject><subject>Memory</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microscopy</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Phosphatase</subject><subject>Presynapse</subject><subject>Protein kinase A</subject><subject>Proteins</subject><subject>Receptor mechanisms</subject><subject>Receptors, Dopamine D3 - genetics</subject><subject>Receptors, Dopamine D3 - metabolism</subject><subject>Synapses - metabolism</subject><subject>synaptic plasticity</subject><subject>Synaptic Transmission</subject><subject>Therapeutic targets</subject><subject>Variance analysis</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><issn>1474-9718</issn><issn>1474-9726</issn><issn>1474-9726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1u1DAQxyMEoh9w4QGQJS6o0haPndjJCZVt-ZBW4gJny3Emuy6Jbexkq731EfqMPAkuW1bAAV9saX7-aWb-RfEC6Dnk80YbHM6hZA08Ko6hlOWikUw8PryhPipOUrqmFGRD-dPiiDeMCw70uNi-G7z5pjskviedD3q0DsklJxENhsnHROwYot9iIhsbgjd6DHogaed0mKwh_ezMZL0j2nX5UzJzJvUaf9zeRRz0hB0xfu3sZLdIwgadn3YBnxVPej0kfP5wnxZf3199WX5crD5_-LS8WC0M5zUsoISqRdq1LW_7VnZ1i32JUvC2Ew2CYUxq2YMRBjRwWsm-KVlNZV3Lygjo-Gnxdu8NcztiZ9BNUQ8qRDvquFNeW_V3xdmNWvutAqgECFFlw-sHQ_Tf82yTGm3KCx-0Qz8nlbcIjDUC6oy--ge99nN0eb5MsRp4LWmTqbM9ZaJPKWJ_6Aaous9T3eepfuWZ4Zd_9n9AfweYAdgDN3bA3X9U6mJ5tdpLfwID665k</recordid><startdate>202411</startdate><enddate>202411</enddate><creator>Tropea, Maria Rosaria</creator><creator>Melone, Marcello</creator><creator>Li Puma, Domenica Donatella</creator><creator>Vacanti, Valeria</creator><creator>Aceto, Giuseppe</creator><creator>Bandiera, Bruno</creator><creator>Trovato, Roberta Carmela</creator><creator>Torrisi, Sebastiano Alfio</creator><creator>Leggio, Gian Marco</creator><creator>Palmeri, Agostino</creator><creator>D'Ascenzo, Marcello</creator><creator>Conti, Fiorenzo</creator><creator>Grassi, Claudio</creator><creator>Puzzo, Daniela</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9542-2251</orcidid></search><sort><creationdate>202411</creationdate><title>Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age‐related cognitive phenotype</title><author>Tropea, Maria Rosaria ; Melone, Marcello ; Li Puma, Domenica Donatella ; Vacanti, Valeria ; Aceto, Giuseppe ; Bandiera, Bruno ; Trovato, Roberta Carmela ; Torrisi, Sebastiano Alfio ; Leggio, Gian Marco ; Palmeri, Agostino ; D'Ascenzo, Marcello ; Conti, Fiorenzo ; Grassi, Claudio ; Puzzo, Daniela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3381-1415be0dbb3bfb7d8bef4e763bd69e1c227a7f1c6c1a13057f9428078875c61d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Age</topic><topic>aging</topic><topic>Aging - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Aging cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tropea, Maria Rosaria</au><au>Melone, Marcello</au><au>Li Puma, Domenica Donatella</au><au>Vacanti, Valeria</au><au>Aceto, Giuseppe</au><au>Bandiera, Bruno</au><au>Trovato, Roberta Carmela</au><au>Torrisi, Sebastiano Alfio</au><au>Leggio, Gian Marco</au><au>Palmeri, Agostino</au><au>D'Ascenzo, Marcello</au><au>Conti, Fiorenzo</au><au>Grassi, Claudio</au><au>Puzzo, Daniela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age‐related cognitive phenotype</atitle><jtitle>Aging cell</jtitle><addtitle>Aging Cell</addtitle><date>2024-11</date><risdate>2024</risdate><volume>23</volume><issue>11</issue><spage>e14291</spage><epage>n/a</epage><pages>e14291-n/a</pages><issn>1474-9718</issn><issn>1474-9726</issn><eissn>1474-9726</eissn><abstract>Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline.
Dopamine D3 receptors (D3Rs) blockade acts through the cAMP/PKA pathway leading to long‐lasting LTP and memory. D3Rs are mainly located in post‐synaptic dendrites and their blockade enhances basal synaptic transmission, AMPAR‐mediated currents, mEPSC amplitude, and the expression of PSD‐95, pGluA1, pCREB. In aged mice, D3R blockade reversed synaptic transmission and plasticity, post‐synaptic protein expression, and PSD length. Aged D3‐KO mice did not exhibit synaptic and memory deficits.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>39236310</pmid><doi>10.1111/acel.14291</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-9542-2251</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Open Access; DOAJ Directory of Open Access Journals; Wiley Online Library (Online service); EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Age aging Aging - metabolism Aging - physiology Animal cognition Animals Antibodies Brain Camps Cognition - physiology Cognitive ability Cyclic AMP response element-binding protein Dendrites Dopamine Dopamine D3 receptors Drug dosages Electron microscopy Experiments Hippocampus Hippocampus - metabolism Kinases Long-Term Potentiation Male Memory Mice Mice, Inbred C57BL Mice, Knockout Microscopy Phenotype Phenotypes Phosphatase Presynapse Protein kinase A Proteins Receptor mechanisms Receptors, Dopamine D3 - genetics Receptors, Dopamine D3 - metabolism Synapses - metabolism synaptic plasticity Synaptic Transmission Therapeutic targets Variance analysis α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors |
| title | Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age‐related cognitive phenotype |
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