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.

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

“…Other basic neurodevelopmental features, such as cortical [80] and cerebellar neurogenesis, seem to be as well regulated by the glycoprotein. Consequently, the minicolumnar organization of the cerebral neocortex appeared to be deeply affected by Reln deficiency [81] and some physiological counterparts of cortical connectivity, such as trans-synaptic signal propagation, were also impaired [82]. However, the outcome of Reln deficiency on the microcircuitry sustaining the cortical machinery is controversial and, surprisingly, the deep architectonic disorganization that follows the lack of the protein occurs in the absence of dramatic functional anomalies.…”

Reelin haploinsufficiency affects skilled motor performance associated with suppression of training-induced gene enrichment, synaptic function and activity-dependent cortical plasticity in mice

“…The training effect was not evident comparing the forelimb area, ipsilateral to the trained forelimb, either in WT (WT trained ipsi vs. WT ipsi p =0.9979), or in HRM (HRM trained ipsi vs. HRM ipsi p = 0.4400). The cortical thresholds used by the ICMS in evoking movements of the skeletal muscles change with cortical structural abnormalities (Nishibe et al, 2018) but not following a brain lesion (Nishibe et al, 2010) or following reach-tograsp training (Kleim et al, 1998). We found that neither Reelin haploinsufficiency nor the reach-to-grasp training affected the cortical stimulation threshold to evoke forelimb movements by ICMS ( Figure 1F n = 8, WT 69.1 ± 7.77 µA, HRM 61.9 ± 7.65 µA, WT trained 73.6 ± 6.67 µA, HRM trained 58.9 ± 3.16 µA; F 3.…”

“…The age of the mice used for the patch clamp was 5 weeks (10 WT and 10 HRM mice) and for the rest of all experiments 17-20 weeks (43 WT, 42 HRM, 10 Dab1 cKO, 10 Dab1 control mice). Genotyping was conducted as previously described (Nishibe et al, 2018).…”

“…Upon completion of 10 days of training, each mouse was subjected to motor cortical mapping (Nishibe et al, 2018). WT group consisted of 4 male mice and 4 female mice (n = 8-9).…”

The <em>Reeler</em> Mouse: A Translational Model of Human Neurological Conditions or Simply a Good Tool for Better Understanding Neurodevelopment?

“…As a consequence, the minicolumnar organization of the cerebral neocortex appeared to be deeply affected by Reln deficiency [169] and some physiological counterparts of cortical connectivity, such as the trans-synaptic signal propagation, were also impaired [170].…”