Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacologic drugs

Individual differences in drug effects and treatment response are relatively enduring, continuously distributed, as well as substantially heritable, and are therefore likely to result from an interplay of multiple genomic variations with environmental influences. As the etiology and pathogenesis of behavioral and psychiatric disorders is genetically complex, so is the response to drug treatment. Psychopharmacologic drug response depends on the structure and functional expression of gene products, which may be direct drug targets or may indirectly modify the development and synaptic plasticity of neural networks critically involved in drug response. While formation and integration of these neural networks is dependent on the action of manifold proteins, converging lines of evidence indicate that genetically controlled variability in the expression of genes critical to the development and plasticity of distinct neurocircuits influences a wide spectrum of quantitative traits including treatment response. During brain development, neurotransmitter systems (e.g. serotonergic system), which are frequently targeted by psychotropic drugs, control neuronal specification, differentiation, and phenotype maintenance. The formation and maturation of these neurotransmitter systems, in turn, is directed by an intrinsic genetic program. Based on the notion that complex gene-gene and gene environment interactions in the regulation of brain plasticity are presumed to contribute to interindividual differences in drug response, the concept of developmental psychopharmacogenetics is emerging. This review appraises prototypical genomic variation with impact on gene expression and complementary studies of genetic and environmental effects on brain development and synaptic plasticity in the mouse model. Although special emphasis is given to molecular mechanisms of neurodevelopmental genetics, relevant conceptual and methodological issues pertinent to the dissection of the psychopharmacogenetic-neurodevelopmental interface are also considered.