Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities

Abstract

Benefits of distributed learning strategies have been extensively described in the human literature, but minimally investigated in intellectual disability syndromes. We tested the hypothesis that training trials spaced apart in time could improve learning in two distinct genetic mouse models of neurodevelopmental disorders characterized by intellectual impairments. As compared to training with massed trials, spaced training significantly improved learning in both the Ts65Dn trisomy mouse model of Down syndrome and the maternally inherited Ube3a mutant mouse model of Angelman syndrome. Spacing the training trials at 1 h intervals accelerated acquisition of three cognitive tasks by Ts65Dn mice: (1) object location memory, (2) novel object recognition, (3) water maze spatial learning. Further, (4) spaced training improved water maze spatial learning by Ube3a mice. In contrast, (5) cerebellar-mediated rotarod motor learning was not improved by spaced training. Corroborations in three assays, conducted in two model systems, replicated within and across two laboratories, confirm the strength of the findings. Our results indicate strong translational relevance of a behavioral intervention strategy for improving the standard of care in treating the learning difficulties that are characteristic and clinically intractable features of many neurodevelopmental disorders.

Evaluation of a TrkB agonist on spatial and motor learning in the Ube3a mouse model of Angelman syndrome

“…Latencies at day 10 were in the range of 20 sec in Ube3a mice trained with distributed learning trials, spaced at 1 h intervals, as compared with latencies at day 10 in the range of 30-35 sec, in Ube3a mice trained with massed learning trials (Fig. 2), consistent with previous findings (Lauterborn et al 2019). No significant difference was detected in the time course across training days for acquisition by Ube3a mice treated with vehicle versus 7,8-DHF (F (1,19) = 0.07, NS), indicating no faster learning with 7,8-DHF.…”

“…(B) Ube3a in both the vehicle and 7,8-DHF groups did not successfully reach the acquisition criterion of under 15 sec to reach the hidden platform location, although acquisition latencies at day 10 were generally lower after spaced training trials than latencies at day 10 after the massed training trials shown in Figure 2. This observation extends previous findings of better learning with spaced versus massed training in 2to 3-mo-old Ube3a mice (Lauterborn et al 2019). No significant difference was detected in the time course across training days for acquisition by Ube3a mice treated with vehicle versus 7,8-DHF.…”

“…Interaction of training day × treatment was not significant (F (1,23) = 3.838, P = 0.0623, NS). Note that only the first cohort of mice was used in rotarod testing, based on previous findings that rotarod performance did not differ between massed and spaced training conditions in either WT or Ube3a mice (Lauterborn et al 2019). Figure 2 illustrates Morris water maze spatial learning impairments in 6-mo-old Ube3a mice as compared to WT, when trained with the conventional four massed daily training trials.…”

“…We then repeated this experiment in a separate cohort of 6-mo-old Ube3a and WT mice using spaced training trials. Previously we had discovered that spacing the training trials by 1 h intervals improved acquisition in young Ube3a mice (Lauterborn et al 2019). To test the hypothesis that the combination of spaced training plus TrkB receptor activation could additively or synergistically improve water maze performance in Ube3a mice, the second independent cohort of 6-mo-old Ube3a and WT was trained with four daily spaced trials and 5 mg/kg 7,8-DHF.…”

“…In a separate group of 6-mo-old WT and Ube3a mice, 7,8-DHF was administered before and during a distributed training procedure, in which the four daily training trials were separated by 1 h intervals. Our previous study using this spaced learning protocol discovered improved acquisition in 7-to 14-wk-old Ube3a mice, as compared to training with massed trials (Lauterborn et al 2019). The combination of spaced training trials + 7,8-DHF treatment was designed to address the hypothesis that a behavioral intervention given together with a pharmacological intervention could produce additive or synergistic benefits in Ube3a mice at older ages.…”