Size does not always matter: Ts65Dn Down syndrome mice show cerebellum-dependent motor learning deficits that cannot be rescued by postnatal SAG treatment.
Humans with Down syndrome (DS) and Ts65Dn mice both show a reduced volume of the cerebellum due to a significant reduction in the density of granule neurons. Recently, cerebellar hypoplasia in Ts65Dn mice was rescued by a single treatment with SAG, an agonist of the Sonic hedgehog pathway, administered on the day of birth. In addition to normalizing cerebellar morphology, this treatment restored the ability to learn a spatial navigation task, which is associated with hippocampal function. It is not clear to what extent this improved performance results from restoration of the cerebellar architecture or a yet undefined role of Sonic hedgehog (Shh) in perinatal hippocampal development. The absence of a clearly demonstrated deficit in cerebellar function in trisomic mice exacerbates the problem of discerning how SAG acts to improve learning and memory. Here we show that phase reversal adaptation and consolidation of the vestibulo-ocular reflex is significantly impaired in Ts65Dn mice, providing for the first time a precise characterization of cerebellar functional deficits in this murine model of DS. However, these deficits do not benefit from the normalization of cerebellar morphology following treatment with SAG. Together with the previous observation that the synaptic properties of Purkinje cells are also unchanged by SAG treatment, this lack of improvement in a region-specific behavioral assay supports the possibility that a direct effect of Shh pathway stimulation on the hippocampus might explain the benefits of this potential approach to the improvement of cognition in DS.
Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands, Department of Physiology and Institute for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21025, and Department of Neuroscience, Erasmus MC Rotterdam, NL-3015 GE Rotterdam, The Netherlands.
Nicolas
N
Gutierrez-Castellanos
Beerend H J
BH
Winkelman
Leonardo
L
Tolosa-Rodriguez
Benjamin
B
Devenney
Roger H
RH
Reeves
Chris I
CI
De Zeeuw
D000818:Animals; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology*; D003514:Cyclohexylamines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy*; D053823:Hedgehog Proteins / Q000819:agonists; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D011689:Purkinje Cells / Q000473:pathology; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects; D013569:Synapses / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
D003514:Cyclohexylamines; D053823:Hedgehog Proteins; C468918:SAG compound; C465570:Shh protein, mouse; D013876:Thiophenes