A specific population of astrocytes in the central striatum expresses μ-crystallin (Crym), which is associated with several human diseases, including neuropsychiatric disorders. Reducing μ-crystallin levels in striatal astrocytes using CRISPR-Cas9-mediated knockout of Crym in adult mice resulted in perseverative behaviors, increased fast synaptic excitation in medium spiny neurons, and dysfunctional excitatory-inhibitory synaptic balance. These behaviors were linked to the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. Presynaptic inhibitory chemogenetics corrected these synaptic deficits and perseveration phenotypes. The study reveals that Crym-positive striatal astrocytes gate perseveration phenotypes associated with neuropsychiatric disorders. The findings highlight the molecular, synaptic, circuit, and behavioral mechanisms by which Crym-positive astrocytes regulate perseveration. The study also identifies the synaptic mechanism by which Crym-positive astrocytes gate perseveration and sheds light on the physiology of μ-crystallin, a protein associated with multiple human disorders, in the central nervous system. The research demonstrates that Crym-positive striatal astrocytes have key biological functions in the central nervous system and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration. The study also shows that Crym-positive astrocytes regulate neurotransmitter release probability of lOFC-striatum terminals through tonic-GABA-mediated presynaptic modulation. The findings suggest that astrocyte diversity is crucial for neural circuits and behavior, and that regionally allocated astrocytes play a key role in regulating neural circuits and disease phenotypes. The study provides insights into the molecular and functional roles of Crym-positive astrocytes in the central striatum and their potential as therapeutic targets for neuropsychiatric disorders.A specific population of astrocytes in the central striatum expresses μ-crystallin (Crym), which is associated with several human diseases, including neuropsychiatric disorders. Reducing μ-crystallin levels in striatal astrocytes using CRISPR-Cas9-mediated knockout of Crym in adult mice resulted in perseverative behaviors, increased fast synaptic excitation in medium spiny neurons, and dysfunctional excitatory-inhibitory synaptic balance. These behaviors were linked to the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. Presynaptic inhibitory chemogenetics corrected these synaptic deficits and perseveration phenotypes. The study reveals that Crym-positive striatal astrocytes gate perseveration phenotypes associated with neuropsychiatric disorders. The findings highlight the molecular, synaptic, circuit, and behavioral mechanisms by which Crym-positive astrocytes regulate perseveration. The study also identifies the synaptic mechanism by which Crym-positive astrocytes gate perseveration and sheds light on the physiology of μ-crystallin, a protein associated with multiple human disorders, in the central nervous system. The research demonstrates that Crym-positive striatal astrocytes have key biological functions in the central nervous system and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration. The study also shows that Crym-positive astrocytes regulate neurotransmitter release probability of lOFC-striatum terminals through tonic-GABA-mediated presynaptic modulation. The findings suggest that astrocyte diversity is crucial for neural circuits and behavior, and that regionally allocated astrocytes play a key role in regulating neural circuits and disease phenotypes. The study provides insights into the molecular and functional roles of Crym-positive astrocytes in the central striatum and their potential as therapeutic targets for neuropsychiatric disorders.