美国加州大学Baljit S. Khakh小组取得一项新突破。他们发现crym阳性纹状体星形胶质细胞调控持续性行为。这一研究成果于2024年2月28日发表在国际学术期刊《自然》上。

研究人员发现中枢纹状体中一个特定的星形胶质细胞群表达μ-结晶素（小鼠由Crym基因编码，人类由CRYM编码），而μ-结晶素与包括神经精神障碍在内的多种人类疾病有关。在成年小鼠中，通过CRISPR-Cas9介导的Crym基因敲除减少了纹状体星形胶质细胞中的μ-结晶素，这会导致顽固行为、中棘神经元的快速突触兴奋增加以及兴奋-抑制突触平衡失调。坚持行为的增加源于星形胶质细胞失去了对眶额叶皮质-脊髓突触前终端神经递质释放的门控。研究发现，可以使用突触前抑制性化学遗传学疗法来挽救毅力障碍，而且这种疗法也能纠正突触缺陷。

总之，该研究结果揭示了分子、突触、回路和行为交汇的机制，通过这些机制，一个确定分子表型和分配的纹状体星形胶质细胞群，可以控制与神经精神障碍持续性有关的表型。该数据表明，Crym阳性纹状体星形胶质细胞在中枢神经系统中具有关键的生物学功能，并揭示了星形胶质细胞与神经元的相互作用机制，这些机制可作为顽固症的治疗靶点。

据介绍，星形胶质细胞是中枢神经系统中的异质性胶质细胞。然而，仍不清楚星形胶质细胞多样性与神经回路和行为之间的生理相关性。

附：英文原文

Title: Crym-positive striatal astrocytes gate perseverative behaviour

Author: 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.

Issue&Volume: 2024-02-28

Abstract: Astrocytes are heterogeneous glial cells of the central nervous system1,2,3. 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 disorders4,5,6,7. 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 chemogenetics8, 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 disorders9,10,11,12. 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.

DOI: 10.1038/s41586-024-07138-0

Source: https://www.nature.com/articles/s41586-024-07138-0