The convergence of psychiatry and developmental neurobiology
Mutations in many different 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 . These 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 different loci . They also indicate that these distinct clinical categories share overlapping etiologies and strongly implicate neurodevelopmental processes in a significant 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. The application of these approaches in mice has revealed a wealth of information on how the brain gets wired. The 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 affecting a process such as cell migration or synaptogenesis is mutated? The primary defects due to impairment of that protein are just the start of the story. How does miswiring of the circuit affect 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 affect 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 fields and disciplinary traditions .