The study investigates the role of μ-crystallin-expressing striatal astrocytes in regulating perseverative behaviors, which are associated with neuropsychiatric disorders such as obsessive-compulsive disorder (OCD) and Huntington's disease (HD). μ-crystallin, encoded by the Crym gene in mice and CRYM in humans, is a protein with unclear functions in the central nervous system. The researchers found that reducing μ-crystallin levels in striatal astrocytes through CRISPR-Cas9-mediated knockout led to increased perseverative behaviors, enhanced fast synaptic excitation in medium spiny neurons, and disrupted excitatory-inhibitory synaptic balance. These changes were attributed to the loss of astrocyte-gated control over neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. The study also demonstrated that presynaptic inhibitory chemogenetics could correct these synaptic deficits and alleviate perseverative behaviors. These findings highlight the importance of μ-crystallin-positive striatal astrocytes in modulating neural circuits and suggest potential therapeutic targets for treating perseveration phenotypes in neuropsychiatric disorders.The study investigates the role of μ-crystallin-expressing striatal astrocytes in regulating perseverative behaviors, which are associated with neuropsychiatric disorders such as obsessive-compulsive disorder (OCD) and Huntington's disease (HD). μ-crystallin, encoded by the Crym gene in mice and CRYM in humans, is a protein with unclear functions in the central nervous system. The researchers found that reducing μ-crystallin levels in striatal astrocytes through CRISPR-Cas9-mediated knockout led to increased perseverative behaviors, enhanced fast synaptic excitation in medium spiny neurons, and disrupted excitatory-inhibitory synaptic balance. These changes were attributed to the loss of astrocyte-gated control over neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. The study also demonstrated that presynaptic inhibitory chemogenetics could correct these synaptic deficits and alleviate perseverative behaviors. These findings highlight the importance of μ-crystallin-positive striatal astrocytes in modulating neural circuits and suggest potential therapeutic targets for treating perseveration phenotypes in neuropsychiatric disorders.