The miswired brain: making connections from neurodevelopment to psychopathology

Abstract

Developmental neurobiologists have made great progress in elucidating the molecular mechanisms underlying nervous system development. Th ere has been less focus, however, on the consequences when these processes go wrong. As the evidence increases that mutations in neurodevelopmental genes are associated with major psychiatric disorders, defi ning these consequences assumes paramount importance in elucidating pathogenic mechanisms. The convergence of psychiatry and developmental neurobiology Mutations in many diff erent genes controlling cell migration, axon guidance and especially synaptogenesis are being found at an increasing rate in patients with schizophrenia, autism, epilepsy, mental retardation and other disorders [1]. Th ese discoveries are prompting a paradigm shift regarding models of the genetic architecture of these disorders, which can be seen to be highly heterogeneous and primarily due to rare mutations in any of a large number of diff erent loci [2]. Th ey also indicate that these distinct clinical categories share over lapping etiologies and strongly implicate neuro develop mental processes in a signifi cant proportion of cases. In this context, investigating the genetics of neurodevelopment in animals assumes greater importance. Many researchers have used genetic approaches in model organisms to dissect how neurodevelopmental processes work - to infer the normal function of a protein and to identify the cellular processes it is involved in. Th e application of these approaches in mice has revealed a wealth of information on how the brain gets wired. Th e converse question - how the brain can be miswired - has received less direct attention. With the evidence of relevance to human disease, the phenotypes that arise in mice due to mutations in neurodevelopmental genes become of interest in themselves, not just as indicators of the normal function of the gene. It is important to ask: what happens to brain circuitry when a mutation aff ecting a process such as cell migration or synaptogenesis is mutated? Th e primary defects due to impairment of that protein are just the start of the story. How does miswiring of the circuit aff ect its function? What are the secondary consequences of altered activity in developing circuits? How does the developing brain react to such changes? How does the ultimate anatomical outcome aff ect brain functions, as indexed by physiology and behavior? Answering these questions will be a major challenge for the future and will require an integration of expertise from diverse fi elds and disciplinary traditions [3].