Corticospinal tract neurons are radially malpositioned in the sensory‐motor cortex of the shaking rat Kawasaki

Abstract

Shaking rat Kawasaki (SRK) is an autosomal recessive mutant rat that exhibits tremor, dystonia, and ataxia and that is characterized by abnormal lamination of the cerebral and cerebellar cortices and the hippocampus. To examine whether or not layer V neurons in the mutant neocortex are malpositioned in accordance with the aberrant laminar cytoarchitecture, horseradish peroxidase (HRP) was injected into the lumbar spinal cord of SRK mutant and normal control rats to label cortical pyramids projecting through the corticospinal tract (CST). HRP-labeled CST neurons of both normal and SRK rats were found mainly in the hindlimb area of the sensory-motor cortex, indicating a normal tangential distribution of labeled CST neurons in the SRK mutant. In the radial axis, however, labeled CST neurons were spread throughout all layers of the mutant cortex, whereas those in normal rats were restricted to layer V. In the mutant, most labeled CST neurons located in the inner third of the cortex had a typical pyramidal form with an upright apical dendrite, but many of those located near the pial surface displayed abnormal shapes and could be subdivided into inverted pyramidal, horizontal, and bipolar neurons on the basis of their dendritic morphology. The abnormal distribution pattern of labeled CST neurons in the mutant was quantified using a standardized measure of their depth distribution, where 0% = the level of the white matter and 100% = the pial surface. The mean value for the SRK cortex of 47.0% was significantly greater than the figure of 40.5% for normal rats (P < 0.01, Student's t test), indicating a spread of CST neurons toward the pial surface in SRK, but even more striking was the size of the standard deviation: 30.4 in SRK compared with 7.1 in controls. The distribution pattern of CST neurons of the SRK rat was also statistically identical with that of the reeler mouse, which is a well-known mutant that also exhibits an abnormal lamination pattern in the cerebral cortex. These results indicate that neuronal components of the neocortex of the SRK mutant are intermingled along the radial axis, but not in the tangential axis, and provide further evidence for a strong similarity between this spontaneous rat mutation and the reeler malformation.

Functional Thalamocortical Synapse Reorganization from Subplate to Layer IV during Postnatal Development in theReeler-Like Mutant Rat (Shaking Rat Kawasaki)

“…The SRK brains appeared smaller, and the cerebellar cortex had abnormal foliation in the mutants. We could identify the SRK (homozygote) mutants through the characteristic abnormal external cerebellar morphology, as reported previously (Aikawa et al, 1988;Ikeda and Terashima, 1997). Figure 1 demonstrates typical morphological differences between SRK and WT rat cerebral cortex and the position of cells born at E13 and E17, determined by birthdating.…”

“…The present study confirms the previous anatomical studies on the reeler mutant mouse (Caviness, 1976;Yuasa et al, 1994;Molnár, 1998) and SRK (Aikawa et al, 1988;Ikeda and Terashima, 1997), demonstrating thalamocortical innervation of superplate, but it also provides the first evidence for functional synapses. Moreover, our optical and electrophysiological recording results suggest that synapse reorganization from subplate neurons to layer IV cells during early developmental stages is a general process for the development of thalamocortical connections in the cortex.…”

“…It has been demonstrated that a short deletion in the reelin gene causes the reeler-like phenotype of SRK (Ikeda and Terashima, 1997;Kikkawa et al, 2003). In a typical litter generated from a SRK heterozygote female and male (usually 10 -12 pups), one to three pups (ϳ25%) show motor deficit and characteristic reeling behavior 2 weeks after birth.…”

The right neuron at the wrong place: biology of heterotopic neurons in cortical neuronal migration disorders, with special reference to associated pathologies

“…Given this well-described projection pattern, there has been considerable interest in determining the projection targets of displaced layer 5 pyramidal neurons. Corticospinal neurons identified by retrograde labelling after spinal injection of horseradish peroxidase (HRP) have been observed in subcortical heterotopias after prenatal irradiation [73], in the external neocortical layers after prenatal ethanol treatment [74] or dispersed in the whole cortical thickness in reeler mutants [75,76]. Interestingly, corticospinal neurons situated in the external cortical layers, identified in vivo by their antidromic response to the stimulation of the pyramidal tract, turned out to have a morphology of supragranular neurons [77], reinforcing the previous claim that heterotopic neurons with altered morphology could be underestimated.…”

Development and Plasticity in Sensory Thalamus and Cortex

“…The phenotype of SRK resembles that of the reeler mouse (Aikawa et al, 1988;Ikeda and Terashima;1997). The role of Reelin in choreographing thalamocortical ingrowth may be complex and is most probably indirect (no direct effect of Reelin on the growth of thalamocortical axons has not been demonstrated).…”