Key brain cells linked to repetitive behaviors in psychiatric diseases

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Mar 6 2024

In a recent Nature study, researchers discovered that Crym-expressing astrocytes in the central striatum play a key role in the manifestation of repetitive behaviors associated with many neuropsychiatric diseases, thus demonstrating its potential as a therapeutic target.

Study: Crym-positive striatal astrocytes gate perseverative behavior. Image Credit: Vitaly Sosnovskiy / Shutterstock.com

What are astrocytes?

Astrocytes are dominant glial cells within the central nervous system (CNS) and interact with other neurons to exert various metabolic, neuroprotective, structural, and homeostatic properties. Astrocytes exhibit different properties that are unique to their specific location within the brain; however, it remains unclear how specialized astrocytes function in their associated neural circuits and how these activities contribute to normal physiology and behavior, as well as the development of certain neurological diseases.  

The basal ganglia houses the striatum, which consists of astrocytes that highly express the Crym gene. Crym encodes µ-crystallin, a cytosolic protein that has been reported to function as a ketamine reductase or bind to nicotinamide adenine dinucleotide phosphate (NADPH) to regulate the thyroid hormone T3.

Previous studies have shown that Crym expression may be associated with amyotrophic lateral sclerosis (ALS), schizophrenia, and Huntington’s disease (HD). Nevertheless, there remains a lack of data on the precise role of Crym in striatal astrocytes and the function of µ-crystallin within the brain.

The localization of Crym and µ-crystallin

Striatum samples were originally obtained from individuals diagnosed with obsessive compulsive disorder (OCD) or HD to identify enriched genes present within striatal astrocytes. As compared to control tissues, CRYM was downregulated to about 40% within the caudate nucleus in both OCD and HD samples. Likewise, mouse models of HD have demonstrated that CRYM is among the top 4% of downregulated genes, thus indicating the crucial role of this gene in HD pathology.

These observations subsequently led to in vivo studies, in which Crym expression was dominant within the striatum, with µ-crystallin-expressing astrocytes accounting for about 49% of astrocytes within this region of the brain. More specifically, µ-crystallin expression was particularly high within the subventricular zone (SVZ), thus confirming that Crym expression may be anatomically allocated to a specific population of striatal astrocytes.  

Investigating the effects of Crym loss-of-function

To elucidate the role of the Crym gene, the researchers developed six Crym knockout (KO) mouse strains using the clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 single-guide ribonucleic acids (sgRNAs) that were delivered through adeno-associated virus (AAV) intracranial administration, three of which were ultimately selected due to their superior KO efficiency.

Three weeks after AAV administration, µ-crystallin levels within astrocytes declined by 80%, except for those present in the SVZ. Although Crym KO did not cause any significant weight loss or behavioral effects in the open-field, footprint, and rotarod tests, these mice had a shorter latency to start and longer digging durations in the marble-burying test. Longer self-grooming and water bottle lick durations were also observed in Crym KO mice.

Crym KO mice also spent more time with a familiar object in the novel object recognition task, which may indication perseveration for that object. These perseverative behaviors observed in Crym KO mice can be correlated with those associated with certain psychiatric and neurological disorders including OCD, HD, Tourette’s syndrome, autism, and suicide-associated perseveration in HD.

Furthermore, Crym KO mice exhibited an increased concentration of cFOS+ neurons, which is a marker for increased neuronal activity, within the lateral orbitofrontal cortex (IOFC), central striatum, and dorsal thalamus (dTH). IOFC striatal projections were found to invade the central striatum that exhibited high levels of Crym+ neurons, an observation that has been previously implicated in OCD.

Crym mechanism of action

Gas chromatography-mass spectrometry (GC-MS) was used to compare the glutamate/gamma-aminobutyric acid (GABA) ratio in Crym KO and control striatal samples. As compared to control mice, the glutamate/GABA ratio was significantly higher in Crym KO mice, which indicates greater release of glutamate from IOFC projections.

A significant reduction of GABA and monoamine oxidase B (MOAB), the latter of which is an astrocytic enzyme that produces GABA, was also observed in Crym KO mice. These observations suggest that increased synaptic excitation from IOFC terminals leads to lower levels of tonic GABA, which causes reduced presynaptic inhibition.

Study significance

Crym-expressing astrocytes in the central striatum regulate the release of GABA from the IOFC into the central striatum. Importantly, the loss of this regulation can lead to perseveration, which involves the continuation or repetition of a response or activity, a phenotype that is often reported in OCD, autism, Tourette’s syndrome, and HD.  

These findings provide guidance for the development of future therapeutic strategies that can target the release of neurotransmitters from IOFC terminals projecting into the central striatum. Furthermore, the identification of brain region-enriched astrocytes can also support future studies aiming to identify specific circuits and nuclei involved in different neurological diseases.