Editors' ChoiceNeuropsychiatric disorders

Astrocyte dysfunction and compulsive behavior

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaav3882
DOI: 10.1126/scitranslmed.aav3882


Molecular, cellular, and circuit physiology studies identify a potential new therapeutic target for compulsive behavior disorders, involving dysfunctional neuron-astrocyte interactions within striatal microcircuits.

Compulsive behaviors are key features of a variety of neuropsychiatric disorders, including obsessive compulsive disorder (OCD), addictions, and neurodegenerative diseases, such as Huntington's disease, but the neurobiological mechanisms underlying the development of compulsive behaviors are not well understood, especially at the level of neural circuits. Yu et al. report compelling and comprehensive new data implicating dysfunctional signaling within astrocytes—a previously understudied cell type in this context and potential therapeutic target.

Converging data from clinical neuroimaging, genetic, and neurophysiology studies indicate that striatal circuit dysfunction plays an important role in generating compulsive behaviors, such as excessive checking, counting, and washing in humans, and grooming in rodents. However, most studies to date have focused on neurons. Astrocytes are star-shaped glial cells that interact closely with neurons, recycling neurotransmitters, supporting synapse formation, and regulating other aspects of neuronal function through mechanisms that, although not completely understood, appear to involve intracellular calcium signaling. One important obstacle to understanding neuron-astrocyte interactions is that it has been challenging to experimentally manipulate astrocyte function with spatiotemporal precision. Yu et al. developed and validated a new method for suppressing calcium signaling specifically within striatal astrocytes through virally mediated overexpression of a calcium pump within this cell type in mice. Suppressing intracellular calcium signaling within striatal astrocytes produced an excessive self-grooming phenotype, reminiscent of the compulsive washing behaviors often seen in OCD patients, and was associated with abnormal activity patterns in striatal medium spiny neurons (MSN). The authors went on to identify a molecular mechanism by which astrocytes modulate striatal MSN function by regulating tonic inhibition and controlling local concentrations of GABA, a key inhibitory neurotransmitter. Importantly, treating these mice for one week with a pharmacological GABA uptake inhibitor was sufficient to rescue the effects of astrocyte dysfunction on both tonic inhibition and compulsive grooming behavior. Although the physiological relevance of this type of astrocyte manipulation for OCD and other neuropsychiatric conditions needs to be further investigated, the authors were able to establish that similar pathology was evident in a Huntington's disease mouse model and could be rescued with the same treatment. Together, these findings identify novel molecular and circuit-level mechanisms by which striatal astrocyte dysfunction may give rise to compulsive behaviors, potentially opening previously understudied avenues for developing new astrocyte-specific treatments for OCD and related neuropsychiatric disorders.

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