Altered interneuron development in the cerebral cortex of the flathead mutant

One approach to defining mechanisms essential to neocortical development is to analyze the phenotype of novel spontaneous mutations that dramatically affect the generation and differentiation of different neocortical neurons. Previously we have shown that there is a large decrease in the total numbe r of cortical neurons in the flathead mutant rat, and in this paper we show that the flathead (fh/fh) mutation causes an even larger decrease in the n umber of interneurons. The decrease in relative interneuron number is diffe rent in different cortical lamina and for different interneuron subtypes. S pecifically, the percentage of GABA and calretinin-positive cells in upper layers of somatosensory cortex is not appreciably decreased in homozygous m utants, while other interneuron subtypes in somatosensory cortex and all GA BA-positive interneuron types in entorhinal cortex are decreased. In additi on, the soma and dendritic arbors of interneurons in flathead are greatly h ypertrophied, while those of pyramidal neurons are not. Furthermore, we fou nd that at embryonic day 14, flathead mutants display high levels of cell d eath throughout both the neocortical and ganglionic eminence (GE) prolifera tive zones with a larger increase in cell death in the GE than in the neoco rtical VZ. In addition, we provide evidence that there is widespread cytoki nesis failure resulting in binucleate pyramidal cells and interneurons, and the number of binucleate interneurons is greater than the number of binucl eate pyramidal neurons. Together, these results demonstrate that the fh mut ation causes dramatic alterations in interneuron development, and suggest t hat the flathead mutation causes differential cytokinesis failure and cell death in different types of neocortical progenitors.