Crym-positive striatal astrocytes gate perseverative behaviour

• Published in: Nature (London) 2024-03, Vol.627 (8003), p.358-366
• Main Authors: Ollivier, Matthias, Soto, Joselyn S., Linker, Kay E., Moye, Stefanie L., Jami-Alahmadi, Yasaman, Jones, Anthony E., Divakaruni, Ajit S., Kawaguchi, Riki, Wohlschlegel, James A., Khakh, Baljit S.
• Format: Article
• Language: English
• Subjects: 14/63; 38; 38/32; 38/35; 38/91; 631/378/2596/1308; 631/378/3920; 631/378/87; 64; 64/60; 692/1807/1693; 692/699/476; 82; 82/51; 82/58; Anxiety; Astrocytes; Behavior; Central nervous system; Crystallin; Gates (circuits); Genes; Glial cells; Humanities and Social Sciences; Huntingtons disease; multidisciplinary; Neostriatum; Nervous system; Neural networks; Neurons; Neurotransmitter release; Obsessive compulsive disorder; Phenotypes; Physiology; Science; Science (multidisciplinary); Spiny neurons
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07138-0

Astrocytes are heterogeneous glial cells of the central nervous system 1 – 3 . 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 μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders 4 – 7 . In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR–Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory–inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex–striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics 8 , 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 9 – 12 . Our data show that Crym -positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte–neuron interaction mechanisms that could be targeted in treatments for perseveration. In mice, a population of astrocytes in the central striatum, characterized by expression of μ-crystallin, has a role in perseveration phenotypes that are often associated with human neuropsychiatric disorders.