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In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT<jats:sup>\u2212\/\u2212<\/jats:sup>) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The expression, localisation, retention and electrophysiological properties of N\u2010methyl\u2010D\u2010aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT<jats:sup>\u2212\/\u2212<\/jats:sup> rats, at baseline and after treatment with the non\u2010competitive NMDA receptor antagonist memantine (30\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B\u2010containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine\u2010induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long\u2010term depression (LTD) in the striatum of DAT<jats:sup>\u2212\/\u2212<\/jats:sup>rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT<jats:sup>\u2212\/\u2212<\/jats:sup> rats, thus restoring functional LTD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17403","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T23:19:51Z","timestamp":1733786391000},"page":"1377-1393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Memantine\u2010induced functional rewiring of the glutamate synapse in the striatum of dopamine transporter knockout rats"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8045-3146","authenticated-orcid":false,"given":"Lucia","family":"Caffino","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences \u2018Rodolfo Paoletti\u2019 Universit\u00e0 degli Studi di Milano  Milan 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