GAP‐43 heterozygous mice show delayed barrel patterning, differentiation of radial glia, and downregulation of GAP‐43

Abstract

GAP-43 heterozygous (HZ) mice exhibit abnormal thalamocortical pathfinding, fasciculation, and terminal arborization at postnatal day 7 (P7). Here we tested whether these defects are correlated with delayed development of HZ cortical patterns. We assessed the rate of barrel segregation and radial glia differentiation in wild-type (WT) and HZ cortices. Since GAP-43 is involved in some forms of neural plasticity, we also compared the duration of the critical period for lesion-induced plasticity in both genotypes. Cytochrome oxidase histochemistry revealed a delay of approximately 1 day in barrel pattern formation in GAP-43 HZ mice. GAP-43 WT barrels showed complete segregation between P2-P3, while HZ barrels did not reach the same level of segregation until P3-P4. We found a similar delay in the transformation of radial glia from monopolar to multipolar phenotypes, from P5 in WT to P7 in HZ cortex. Radial glial cells represent many of the neuronal progenitors in developing cortex and aid in cell migration. Thus, the delay in radial glial differentiation may contribute to the delay in HZ barrel segregation. Interestingly, we found no change in the extent of the critical period for HZ cortical responsiveness to early peripheral damage or in the time course of the cortical response. As expected, GAP-43 expression in HZ cortex is significantly reduced early in development. However, HZ GAP-43 expression remains at maximum levels after P9, when it is normally downregulated. As a result, HZ GAP-43 expression is near-normal by P26, by which time near-normal barrel dimensions have been restored. Our findings indicate that GAP-43 deficiency leads to early delays in barrel development and suggest that these failures are followed by homeostatic responses, including prolonged GAP-43 expression. These compensatory mechanisms may rescue normal cortical reorganization in neonates and near-normal barrel morphology and GAP-43 expression in adulthood.