A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behavior and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behavior deficits. We find that in patDp/+ mice delay eyeblink conditioning—a form of cerebellum-dependent motor learning—is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibers—a model for activity-dependent synaptic pruning—is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.

Summary Plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst–pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses. Pause plasticity is absent from mice lacking SK2-type potassium channels (SK2−/− mice) and in occlusion experiments using the SK channel blocker apamin, while apamin wash-in mimics pause reduction. Our findings demonstrate that spike pauses can be regulated through an activity-dependent, exclusively non-synaptic, SK2 channel-dependent mechanism and suggest that pause plasticity—by altering the Purkinje cell output—may be crucial to cerebellar information storage and learning.

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controlling for patient age, diagnosis year, race/ethnicity, stage, grade, number of positive regional lymph nodes, and tumor size.Results A total of 2,362 patients were identified. A significant improvement in cause specific survival (CSS) was noted in patients who underwent combination therapy (vaginal brachytherapy [VB] plus external beam radiation therapy [EBRT]) versus chemotherapy alone (hazard ratio [HR] 0.805, 95% confidence interval [CI] 0.674-0.961, p<0.05). VB and EBRT each given exclusively versus chemotherapy alone resulted in improved overall survival (OS) ([VB HR 0.852, 95% CI 0.788-0.920, p<0.001], [EBRT HR 0.758, 95% CI 0.646-0.889, p=0.001]), but not cause specific survival (CSS). No difference in survival was found in VB or EBRT alone versus combination therapy, or in EBRT versus VB. Conclusions Combination aRT with chemotherapy shows superior CSS compared to chemotherapy alone. This SEER database study validates aRT use in this rare subset of high-risk endometrial cancer.

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