22455
Mechanisms Underlying Sensitive Periods for Treatment of Cerebellar Mediated Autistic Behavior
Autism Spectrum Disorders (ASDs) are prevalent neurodevelopmental disorders marked by social impairments, repetitive behaviors, and cognitive inflexibility. Despite a prevalence exceeding 1%, underlying mechanisms are poorly understood while targeted therapies and their guiding parameters are needed. Recent evidence has implicated the cerebellum in ASD pathogenesis, and we have recently demonstrated that cerebellar dysfunction is sufficient to generate autistic-like behaviors in a mouse model of Tuberous Sclerosis Complex (TSC).
Objectives:
The developmental windows during which behavioral dysregulation emerges and the time windows of treatment efficacy for ASD and the underlying circuit and cellular mechanisms remain poorly understood. In this study, we sought to delineate these sensitive periods for treatment of ASD behaviors and to examine the underlying cellular, physiologic, and circuit based mechanisms.
Methods:
In this study, we utilize the mechanistic target of rapamycin (mTOR) specific inhibitor rapamycin in a cerebellar Tsc1 mouse model of monogenic ASD, performing behavioral analysis, electrophysiologic studies, anatomic characterization, and MRI based structural connectivity.
Results:
Using these methods, we define distinct treatment sensitive periods for autistic-like – motor, social, and repetitive/restricted – behaviors, periods that extend into adulthood for social and motor behaviors. Moreover, we identified anatomic, cellular, and electrophysiologic parameters that underlie behavioral rescue. Lastly, using volumetric MRI and structural covariance measures, we identified patterns of connectivity between cerebellar and cortical regions implicated in clinical ASD that are disrupted in mutant mice. We further demonstrate that alterations in clinically relevant connectivity respond to rapamycin therapy, consistent with demonstrated behavioral rescue.
Conclusions:
These findings, thus, not only define treatment parameters but also provide a mechanistic and structural basis for targeted, behavioral rescue in ASD.