Alterations in the Indirect Basal Ganglia Pathway in An Animal Model of Repetitive Behavior

Background: Although restricted repetitive behaviors are diagnostic for autism and commonly observed in related neurodevelopmental disorders, little is known about specific pathophysiological mechanisms mediating their development or expression. Our lab has employed a deer mouse (Peromyscus maniculatus) model that involves spontaneous expression of high rates of motor stereotypies. We have previously shown that these behaviors are associated with alterations in cortico-basal ganglia circuitry. This circuitry includes two key pathways, the direct and indirect, alterations of which have been implicated in other neurological disorders. Results of a prior study from our lab suggested that expression of high levels of repetitive behavior in these mice was associated with reduced activity of the indirect basal ganglia pathway.

Objectives: To confirm and extend our prior study, we assessed whether alterations in basal ganglia indirect pathway function were associated with stereotypy using both biochemical and pharmacological methods.

Methods: We assessed repetitive behavior in deer mice and then measured neuronal metabolic activation in the subthalamic nucleus (STN), a key nucleus of the indirect pathway. Cytochrome oxidase (CO) histochemistry was used to index long-term neuronal activation. In a second set of studies, we altered the activity of the indirect pathway by administration of a selective adenosine_2A (A_2A) agonist or antagonist to deer mice and assessed its effects on repetitive behavior. A_2A receptors are enriched in striatum and expressed on medium spiny GABA cells that make up the indirect pathway.

Results: CO staining in the STN was significantly reduced in high versus low (median split) stereotypy mice. Further, CO staining was significantly negatively correlated with the frequency of stereotypy. Consistent with this finding, a selective A_2A agonist reduced repetitive motor behavior in deer mice presumably by increasing the activity of the indirect pathway. Conversely, a selective adenosine_2A antagonist induced repetitive behavior in the form of compulsive grooming.

Conclusions: Higher rates of spontaneous repetitive motor behavior were associated with reduced neuronal activation of the indirect basal ganglia pathway. The importance of this pathway in repetitive behavior was strengthened by a reduction of spontaneous stereotypy consequent to activation of adenosine receptors expressed on striatal indirect pathway neurons. Induction of compulsive grooming following blockade of those same receptors provided further support for the importance of the indirect pathway. These findings complement and extend our previous work and support the hypothesis that spontaneous stereotypic behavior in this model is associated with reduced indirect pathway activity. Moreover, adenosine_2A receptors may provide a therapeutic target for the treatment of restricted repetitive behavior in autism.