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During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal\u00a0Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue\n                    <jats:italic>p<\/jats:italic>\n                    -CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole \u2013 another D2-receptor agonist and a known anticonvulsant \u2013 not only increases\n                    <jats:italic>p<\/jats:italic>\n                    -CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces\n                    <jats:italic>p<\/jats:italic>\n                    -CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD.\n                  <\/jats:p>","DOI":"10.1038\/s41380-024-02408-9","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T05:03:36Z","timestamp":1705381416000},"page":"1265-1280","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer\u2019s Disease"],"prefix":"10.1038","volume":"29","author":[{"given":"Elena","family":"Spoleti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"La Barbera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Cauzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"De Paolis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Saba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Sciamanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Di Lazzaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8369-1561","authenticated-orcid":false,"given":"Annalisa","family":"Nobili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8476-9233","authenticated-orcid":false,"given":"Paraskevi","family":"Krashia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6526-1832","authenticated-orcid":false,"given":"Marcello","family":"D\u2019Amelio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"2408_CR1","unstructured":"Gauthier S, Webster C, Servaes S, Morais JA, Rosa-Neto P. 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