Crym-positive striatal astrocytes gate perseverative behaviour

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4431
• DOI: 10.1038/s41586-024-07138-0
• 发表日期: 2024-03-14
• 关键词: mutant huntingtin; transporter; reveals; mouse; mu

摘要

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 mu-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 mu-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.