Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

The BTBR T+tf/J inbred mouse strain displays a variety of persistent phenotypic alterations similar to those exhibited in autism spectrum disorders (ASDs). The unique genetic background of the BTBR strain is thought to underlie its lack of reciprocal social interactions, elevated repetitive self‐directed grooming, and restricted exploratory behaviors. In order to clarify the existence, range, and mechanisms of abnormal repetitive behaviors within BTBR mice, we performed detailed analyses of the microstructure of self‐grooming patterns and noted increased overall grooming, higher percentages of interruptions in grooming bouts and a concomitant decrease in the proportion of incorrect sequence transitions compared to C57BL/6J inbred mice. Analyses of active phase home‐cage behavior also revealed an increase in stereotypic bar‐biting behavior in the BTBR strain relative to B6 mice. Finally, in a novel object investigation task, the BTBR mice exhibited greater baseline preference for specific unfamiliar objects as well as more patterned sequences of sequential investigations of those items. These results suggest that the repetitive, stereotyped behavior patterns of BTBR mice are relatively pervasive and reflect both motor and cognitive mechanisms. Furthermore, other pre‐clinical mouse models of ASDs may benefit from these more detailed analyses of stereotypic behavior.