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Developmental abnormality contributes to cortex-dependent motor impairments and higher intracortical current requirement in the reeler homozygous mutants

Abstract

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.

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Correspondence to Toshihide Yamashita.

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Online Source 1. Morphology of the cortex A. Coronally cut motor cortical sections (acquired from posterior 1.5mm to bregma), each of WT and reeler, were stained with Cresyl Violet. B. WT and reeler sections were stained with antibodies against Neurofilament (Alexa-568). C. Similarly, coronally cut motor cortical sections of Dab1 control and Dab1 cKO were stained with Cresyl Violet. D. Motor cortical sections of Dab1 control and Dab1 cKO were stained with antibodies against Neurofilament (Alexa-488). Note that the cortical layers are disrupted in reeler and Dab1 cKO. Scale bar= 200 µm (TIF 2664 KB)

Online Source 2. Morphology of the cerebellum. Coronally cut cerebellum sections each (posterior ~5.8mm to bregma) of WT, reeler, Dab1 control and Dab1 cKO were stained with Cresyl Violet. While reeler mice show ectopic, no laminated structure (upper right), the cerebellum of Dab1 cKO mice (lower right) contains a typical cytoarchitecture of cerebellum layers indistinguishable from the layers observed in the control (lower left). Scale bar= 1 mm (TIF 2318 KB)

Online Source 3 Ketamine volume. Ketamine/xylazine used volume during intracortical microstimulation mapping, per body weight, per operation hour (±SEM). The ketamine use was ensured consistent throughout the experiments for both groups. A. in reeler ICMS experiments (quantified from n=5) and B. Dab1 ICMS experiments (quantified from n=3). (TIF 2032 KB)

Online Source 4 Neurophysiological results in Dab1 cKO A. Color-coded bilateral maps of movements evoked by ICMS at the current threshold of 90 µA in Dab1 control (Left), of 90 µA in Dab1 cKO (Middle), and of 300 µA in Dab1 cKO (Right). Each representative case is illustrated on a dorsolateral view of the brain. All forelimb maps were bordered either by face, whisker or trunk, tail, hindlimb movements, or non-responsive sites. Dots reflect the ICMS penetration sites, each 500 µm2 apart. The numbers in mm2 are the total forelimb area (±SEM, illustrated in blue, data from n=3). B. Movement representation areas of Dab1 cKO and control (±SEM, quantified from n=3). The forelimb motor representation area was significantly reduced in Dab1 cKO bilaterally (right cortical representation *p=0.002 and left cortical representations *p=0.002). The control and cKO forelimb representation area (±SEM), mapped at 90 µA and 300 µA, respectively, were found not significantly different (right cortical representation p=0.406 and left cortical representation p=0.223). (TIF 3837 KB)

Online Source 5 Reeler and Dab1 cKO neuromuscular junction. A. The photographs show the neuromuscular junctions of an extensor muscle in reeler and WT, demonstrating no obvious deviation from one to the other. (Scale bar of the most left photograph =200 µm, scale bar of the three right photographs =50 µm) B. The photographs show the neuromuscular junctions of an extensor muscle in Dab1 cKO and Dab1 control, demonstrating no obvious deviation from one to the other. (Scale bar of the most left photograph =200 µm, scale bar of the three right photographs =50 µm) C. The bands were found at 70 kDa and 40 kDa, respectively for choline acetyltransferase and α-actin. The bar graph indicates the ratio of choline acetyltransferase expression per α-actin loading control. The samples consisted of homogenized extensor digitorum communis and carpi ulnaris of reeler mice and WT mice. The band quantification did not result in a significant difference between reeler and WT (p=0.827, quantified from n=3). D. The graph shows the comparison of the extensor digitorum weight per body weight (±SEM, p=0.851), comparing reeler, WT (quantified from n=7), Dab1 cKO, and Dab1 control (quantified from n=4). (TIF 2670 KB)

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 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 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 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)

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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Nishibe, M., Katsuyama, Y. & Yamashita, T. Developmental abnormality contributes to cortex-dependent motor impairments and higher intracortical current requirement in the reeler homozygous mutants. Brain Struct Funct 223, 2575–2587 (2018). https://doi.org/10.1007/s00429-018-1647-8

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Keywords

  • Reeler
  • Cortex
  • Motor deficits
  • Development
  • Skilled reach