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

J C Lauterborn,A E Friedman,C M Gall,A A Le,P T Leach,A E Friedman,G S Lynch,M Amani,M Amani,G S Lynch,J N Crawley,M N Schultz,P T Leach

doi:10.1038/s41398-019-0495-5

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.

Highlights

As first recognized in the late 19th century[1], and subsequently confirmed by a very large body of human studies[2,3,4,5,6,7,8,9,10], multiple training episodes spaced apart in time produce better learning than a single massed session
We evaluated learning after massed versus spaced training in two genetically distinct mouse models of intellectual disability: (1) the Ts65Dn trisomy model of Down syndrome[39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55], and (2) the Ube3a maternallyderived knockout model of Angelman syndrome[56,57,58,59,60,61,62,63,64]
Ts65Dn failed to display object location memory (OLM), showing equivalent numbers of seconds spent exploring the object in the new location and the object in the original location during the retention trial when the familiarization training trials were massed in one 10-min session

Summary

Introduction

As first recognized in the late 19th century[1], and subsequently confirmed by a very large body of human studies[2,3,4,5,6,7,8,9,10], multiple training episodes spaced apart in time produce better learning than a single massed session. Work using a type of learning that is dependent on field CA1 confirmed the behavioral relevance of the LTP results[36] Whether these effects occur at other forebrain sites possibly with different timing rules has yet to be tested

Methods

Results

Conclusion