RESUMO
Adult neurogenesis is one of the most rapidly growing areas in neuroscience research and there is great interest in its potential role in the pathophysiology of psychiatric illness. In parallel with early development, adult neurogenesis occurs through the proliferation of precursor cells which migrate to specific regions and differentiate into neurons with characteristics indistinguishable from existing mature neurons. These findings have led to the re-definition of the concept of network plasticity in the adult brain, to include the formation of new neurons as well as new connections. This review examines the idea that adult neurogenesis may be disturbed in schizophrenia. We discuss evidence for abnormal mechanisms of neurogenesis and expression of developmental genes in schizophrenia, the influence of antipsychotic drugs on neurogenesis and the role of candidate schizophrenia susceptibility genes in adult neurogenesis. The recent discovery of molecular markers transiently expressed in newborn neurons within adult neurogenic brain regions could be used to probe whether neurogenesis is disturbed in schizophrenia. Adult neurogenesis could also be used as a unique tool for investigating genes involved in early brain development using post-mortem brains. This is particularly relevant for brain disorders with developmental origins such as schizophrenia.
Assuntos
Encéfalo/fisiopatologia , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Moléculas de Adesão Celular Neuronais/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proteínas da Matriz Extracelular/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Recém-Nascido , Camundongos , Camundongos Mutantes Neurológicos , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Neurônios/citologia , Gravidez , Proteína Reelina , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Serina Endopeptidases/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders.