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However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses \u03bc-crystallin (encoded by <jats:italic>Crym<\/jats:italic> in mice and <jats:italic>CRYM<\/jats:italic> in humans)\u00a0that is associated with several human diseases, including neuropsychiatric disorders<jats:sup>4\u20137<\/jats:sup>. In adult mice, reducing the levels of \u03bc-crystallin in striatal astrocytes through CRISPR\u2013Cas9-mediated knockout of <jats:italic>Crym<\/jats:italic> resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory\u2013inhibitory synaptic balance. Increased\u00a0perseveration stemmed from the loss of\u00a0astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex\u2013striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics<jats:sup>8<\/jats:sup>, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders<jats:sup>9\u201312<\/jats:sup>. Our data show that <jats:italic>Crym<\/jats:italic>-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte\u2013neuron interaction mechanisms that could be targeted in treatments for perseveration.<\/jats:p>","DOI":"10.1038\/s41586-024-07138-0","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T17:04:44Z","timestamp":1709139884000},"page":"358-366","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Crym-positive striatal astrocytes gate perseverative behaviour"],"prefix":"10.1038","volume":"627","author":[{"given":"Matthias","family":"Ollivier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joselyn S.","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay E.","family":"Linker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9699-5406","authenticated-orcid":false,"given":"Stefanie L.","family":"Moye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasaman","family":"Jami-Alahmadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2058-6021","authenticated-orcid":false,"given":"Anthony E.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit S.","family":"Divakaruni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riki","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Wohlschlegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0939-1218","authenticated-orcid":false,"given":"Baljit S.","family":"Khakh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"7138_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1146\/annurev-neuro-070918-050443","volume":"42","author":"BS Khakh","year":"2019","unstructured":"Khakh, B. 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