Summary: UCLA researchers have identified a discrete population of astrocytes in the central striatum that express the gene Crym (encoding μ-crystallin) and play a critical role in regulating behaviors tied to neuropsychiatric conditions. Reducing Crym expression in these astrocytes produced increased repetitive behaviors in mice—behaviors that resemble human perseveration observed in disorders such as autism spectrum disorder and obsessive-compulsive disorder. This discovery challenges the neuron-centric view of behavioral control and highlights astrocytes as potential therapeutic targets.
The study, published in Nature, focused on astrocytes—star-shaped glial cells that support neuronal networks across the central nervous system. While neurons have traditionally been viewed as the primary drivers of behavior, this research demonstrates that a molecularly defined subset of striatal astrocytes actively gates synaptic communication and thereby influences behavior.
The researchers identified astrocytes in the central striatum that uniquely express Crym, a gene that encodes μ-crystallin. μ-crystallin has been linked with multiple human diseases, including neuropsychiatric disorders, but its functional role within neural circuits was not well understood. Using targeted genetic tools, the team selectively reduced Crym levels in these central striatal astrocytes in adult mice and monitored the resulting neural and behavioral changes.
Mice with Crym reduction displayed pronounced perseverative behaviors—repetitive actions that persist even when they are no longer appropriate or interfere with transitions to other behaviors. Perseveration is a hallmark symptom across several neuropsychiatric and neurological conditions, including autism spectrum disorder, obsessive-compulsive disorder, Huntington’s disease, and Tourette syndrome. The study links this behavioral phenotype to altered astrocyte regulation of synaptic function.
Electrophysiological analyses revealed that Crym-deficient astrocytes produced increased fast synaptic excitation in medium spiny neurons and disrupted the excitatory–inhibitory balance in striatal circuits. Mechanistically, the loss of μ-crystallin impaired astrocyte-mediated control over neurotransmitter release from presynaptic terminals of orbitofrontal cortex to striatum projections. Importantly, the researchers demonstrated that chemogenetic suppression of presynaptic activity could rescue both synaptic abnormalities and perseverative behavior, indicating that the behavioral effect arises from dysfunctional neuron–astrocyte circuit interactions rather than an irreversible neuronal deficit.
Key Findings
- Identification of a distinct astrocyte population: Crym-positive astrocytes localized to the central striatum were found to have unique molecular and functional properties.
- Behavioral consequence of Crym reduction: Targeted downregulation of Crym in these astrocytes led to increased perseveration in mice, linking astrocyte function to repetitive, inflexible behaviors.
- Synaptic and circuit mechanisms: Loss of μ-crystallin altered presynaptic neurotransmitter release and increased excitatory drive onto medium spiny neurons, disrupting excitatory–inhibitory balance in striatal circuits.
- Therapeutic implications: Chemogenetic inhibition of presynaptic inputs corrected synaptic and behavioral deficits, suggesting potential avenues to target astrocyte–neuron signaling in neuropsychiatric disorders.
“At a basic biology level, the study shows that molecularly distinct astrocytes perform specific neurobiological functions,” said Baljit Khakh, senior author and professor of physiology and neurobiology at the David Geffen School of Medicine at UCLA. First author Matthias Ollivier, a postdoctoral scholar, noted that reducing Crym levels in central striatal astrocytes revealed mechanisms tied to perseveration.
These findings expand our understanding of cellular diversity in the brain and underscore astrocytes as active participants in circuit regulation and behavior. By revealing convergent molecular, synaptic, circuit, and behavioral mechanisms, the work identifies Crym-positive striatal astrocytes as a biologically defined population that gates perseverative phenotypes relevant to human neuropsychiatric disorders. Ongoing research aims to map the signaling pathways and interactions mediated by μ-crystallin and to explore how modulation of these astrocytes could inform new treatments.
About this neuroscience and mental health research news
Author: Will Houston
Source: UCLA
Contact: Will Houston – UCLA
Image: The image is credited to Neuroscience News
Original Research: Open access. “Crym-positive striatal astrocytes gate perseverative behaviour” by Matthias Ollivier et al., Nature.
Abstract
Crym-positive striatal astrocytes gate perseverative behaviour
Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. This study identifies a population of central striatal astrocytes that express μ-crystallin (encoded by Crym in mice and CRYM in humans), a protein associated with several human diseases including neuropsychiatric disorders. In adult mice, CRISPR–Cas9–mediated reduction of Crym in striatal astrocytes produced perseverative behaviours, elevated fast synaptic excitation in medium spiny neurons, and disrupted excitatory–inhibitory synaptic balance. Increased perseveration resulted from the loss of astrocyte-gated control over neurotransmitter release from orbitofrontal cortex–striatum projections. Presynaptic inhibitory chemogenetics remedied both behavioural and synaptic deficits. These results reveal molecular, synaptic, circuit, and behavioural mechanisms by which a specific population of striatal astrocytes gates perseveration phenotypes and suggest astrocyte–neuron interaction mechanisms that could be targeted to treat perseveration.