Rapid response genes as markers of cellular signaling during cortical histogenesis: Their potential in understanding mental retardation

Aberrations of dendritic morphology are seen in most forms of mental retardation (MR). Normal cortical development is dependent on neural activity that modulates developmental processes such as dendritic differentiation. Indeed, many of the classical histological correlates of MR are reproduced in models that alter activity during development. To explore the hypothesis that MR results from aberrant activity signals during development, it would be useful to have histochemical markers that are sensitive to neural activity. Recent studies indicate that certain immediate early genes (IEGs) are normally expressed at relatively high levels in cortical neurons during postnatal development and are rapidly regulated by natural activity. We have begun to assess the possible use of IEG markers to study MR by examining the pre- and postnatal developmental time course of a panel of known IEG transcription factors as well as a set of novel IEGs identified in our laboratory. One of these recently characterized clones encodes a novel, mitogen-inducible cyclo-oxygenase that is expressed during a critical period for dendritic formation and is regulated by N-methyl-d-aspartate-dependent synaptic activity and by environmental stimuli. These data suggest a role for prostaglandin signaling in postnatal cortical development. Other partially characterized novel IEGs are expressed in a cell-specific fashion in the cortical plate. Application of these histochemical markers to the study of MR pathogenesis in animal models is discussed.