Building the brain is like erecting a house of cards. The early connections provide the foundation of the adult structure, and disruption of these may be the source of many developmental fl aws. Cerebral cortical developmental disorders (including schizophrenia and autism) and perinatal injuries involve cortical neurons with early connectivity. The major hindrance of progress in understanding the early neural circuits during cortical development and disease has been the lack of reliable markers for specifi c cell populations. Due to the advance of powerful approaches in gene expression analysis and the utility of models with reporter gene expressions in specifi c cortical cell types, our knowledge of the early cortical circuits is rapidly increasing. With focus on the subplate, layer VI and layer V projection neurons, we shall illustrate the progress made in the understanding of their neurochemical properties, physiological characteristics and their integration into the early intracortical and extracortical circuitry. This fi eld benefi ted from recent developments in mouse genetics in generating models with subtype specifi c gene expression patterns, powerful cell dissection and separation methods combined with microarray analysis. The emergence of cortical cell type specifi c biomarkers will not only help neuropathological diagnosis, but will also eventually reveal the causal relations in the pathogenesis of various cortical developmental disorders. 2007 Cortical development: genes and genetic abnormalities. Wiley, Chichester (Novartis Foundation Symposium 288) p 212–229 The billions of neurons and trillions of connections of the human brain are generated from the complex interactions between our unfolding genetic programme and our environment. Development is the ultimate readout of our genome; a combination of genetic susceptibility and environmental perturbations can lead to several devastating diseases. The causes of and cures for a large number of cerebral cortical developmental disorders are not known, but their prevalence in the general populaEARLY CORTICAL CIRCUIT FORMATION 213 tion is high (schizophrenia [1 : 100]; autism [1 : 166]; attention defi cit hyperactivity disorder [1 : 30]; dyslexia [1 : 10]; childhood epilepsy; and neural tube closure defects). In spite of recent progress, we are only beginning to understand basic neural developmental mechanisms and their involvement in the pathogenesis of several debilitating diseases. For example, several forms of childhood epilepsy have been linked to cortical neuronal migration disorders, some of which show genetic linkage (see Walsh and colleagues, this volume). The causal relationships are diffi cult to reveal. The single-gene determinist approach will not yield a holistic conception of neural disorders as neuronal production, migration, differentiation and development of cortical connectivity are dependent upon complex signalling cascades. Importance of studying early cortical circuit formation In order to gain a more comprehensive understanding of the brain as fi nal product, we must thoroughly characterize neurodevelopmental processes contributing to its formation. In doing so, we will ascend to a platform from which we can critically analyse and perhaps treat the numerous disorders affecting the developing and mature brain. During the last decade a few pivotal studies have overturned our fundamental knowledge of the site of cortical neurogenesis, the patterns of neuronal cell migration and the genes involved in neuronal differentiation and development of connectivity (Kriegstein et al 2006, Hevner et al 2003, Price et al 2005, Rakic 2006). Recent advances have provided a wealth of information on the temporal and spatial expression of transcription and other factors and their receptors in cortical development (Guillemot et al 2006, Molyneaux et al 2007). We are beginning to understand the general mechanisms and the role of some factors that determine cortical area specialization. We have greater insight into the regulation of the process of cortical neurogenesis and the classifi cation of laminar specifi c sub-classes of cells (Markram 2004, Nelson et al 2006). We also have some insight into the molecular mechanisms involved in the development of both the axonal projections and dendritic arrays of these sub-classes of neurons. The critical questions to elucidate how the expression of genes involved in these processes is regulated by discretely expressed transcription factors. Most, if not all, neurodegenerative diseases disrupt at least one of these processes. Understanding these developmental programmes is therefore of immense clinical signifi cance, because a better understanding could aid in the diagnosis of many of the major neurological disorders (Hevner 2007). Moreover, understanding cell fate determinants and class specifi c biomarkers to detect, classify, and generate all classes and subclasses of neurons could help in developing cell replacement therapies. A century ago the advent of imaging methods allowed for suffi cient contrasting of cells. Even then, based on purely morphological descriptions, it was clear that