Developmental abnormality contributes to cortex-dependent motor impairments and higher intracortical current requirement in the reeler homozygous mutants
The motor deficit of the reeler mutants has largely been considered cerebellum related, and the developmental consequences of the cortex on reeler motor behavior have not been examined. We herein showed that there is a behavioral consequence to reeler mutation in models examined at cortex-dependent bimanual tasks that require forepaw dexterity. Using intracortical microstimulation, we found the forelimb representation in the motor cortex was significantly reduced in the reeler. The reeler cortex required a significantly higher current to evoke skeletal muscle movements, suggesting the cortical trans-synaptic propagation is disrupted. When the higher current was applied, the reeler motor representation was found preserved. To elucidate the influence of cerebellum atrophy and ataxia on the obtained results, the behavioral and neurophysiological findings in reeler mice were reproduced using the Disabled-1 (Dab1) cKO mice, in which the Reelin-Dab1 signal deficiency is confined to the cerebral cortex. The Dab1 cKO mice were further assessed at the single-pellet reach and retrieval task, displaying a lower number of successfully retrieved pellets. It suggests the abnormality confined to the cortex still reduced the dexterous motor performance. Although possible muscular dysfunction was reported in REELIN-deficient humans, the function of the reeler forelimb muscle examined by electromyography, morphology of neuromuscular junction and the expression level of choline acetyltransferase were normal. Our results suggest that the mammalian laminar structure is necessary for the forepaw skill performance and for trans-synaptic efficacy in the cortical output.
KeywordsReeler Cortex Motor deficits Development Skilled reach
This work was supported by the Japan Society for the Promotion of Science Kakenhi Grant-in Aid for Scientific Research B Grant number T1SK199660 to M.N., and a Grant-in-Aid for Scientific Research S from the Japan Society for the Promotion of Sciences 17H06178 to T.Y.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Care and Use of Laboratory Animals of Osaka University Graduate School of Medicine.
This article does not contain any studies with human participants performed by any of the authors.
Online Source 6 Reeler video of somen stick handling task. The video shows a WT mouse and reeler mutant mouse performing the somen stick handling task. In each trial, a mouse ate an uncooked Japanese thin noodle (somen≤1 mm in diameter, cut in 2.8 cm length) in a Plexiglas test chamber or a home-cage environment. The forepaw adjustments were defined as a visible release and re-grasp on the stick, and extension-flexion, abduction-adduction movements of the digits. (MP4 37496 KB)
Online Source 7 Reeler video of sunflower seed handling task. The video shows a WT mouse and reeler mutant mouse performing the sunflower seed handling task. Time counting started from the pick-up of the sunflower seed (0.06-0.08 g) followed by the seed contact with the mouth and ended with letting go of the seed after eating was complete. The time counting was halted when the seed was dropped or the pick-up that was not followed by the mouth contact. Tests were done either in the home-cage environment or in a Plexiglas test chamber. (MP4 52759 KB)
Online Source 8 Dab1 cKO video of somen stick handling task. The video shows a Dab1 control mouse and Dab1 cKO mouse performing the somen stick (somen≤1 mm in diameter, cut in 2.8 cm length) handling task. Notice that Dab1 cKO required a longer time to consume the stick. (MP4 40184 KB)
Online Source 9 Dab1 cKO video of sunflower seed handling task. The video shows a Dab1 control mouse and Dab1 cKO mouse performing the sunflower seed (0.06-0.08 g) handling task. Notice that Dab1 cKO required a longer time to consume the seed. (MP4 130326 KB)
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