Study of the expression and functional mechanisms of the extracellular matrix protein, reelin, during prenatal development of the rodent brain

Resumo

Reelin is an extracellular matrix protein that plays a role in neuronal migration and positioning during development of the central nervous system (CNS) (reviewed by Huang and D'Arcangelo, 2008). Besides this role in early development, reelin is also expressed in the adult brain, where it has been related with synaptic plasticity by enhancing the induction and maintenance of long-term potentiation (Weeber et al., 2002; Beffert et al., 2006), and with dendrite and dendritic spine development (Dong et al., 2003; Niu et al., 2004; 2008; Beffert et al., 2006; Campo et al., 2009). In 1998 was reported the decreased expression of reelin protein and mRNA (about 50%) in post-mortem brains of schizophrenic patients (Impagnatiello et al., 1998). After that seminal finding, other reports also found significant reductions of reelin levels in post-mortem brains of patients with schizophrenia, bipolar disorder, major depression (Fatemi et al., 2000; Guidotti et al., 2000; Fatemi et al., 2001b; Torrey et al., 2005), and also in autism (Fatemi et al., 2001a; 2002; 2005).The study of well-defined animal models for the different mental illnesses is important for the development of new treatments and prevention. Previous to the development of animal models we should gain a better understanding of the physiological roles played by the molecules that are implicated in neurodevelopment and plasticity. Reelin plays an important role in embryogenesis and is also highly expressed during adult life. There are numerous evidences that relate reelin with psychiatric disorders; and in fact the heterozygous reeler mouse was proposed as an animal model for schizophrenia. However it is still necessary to understand in more detail the developmental reelin expression pattern and the functional roles of reelin. We characterized reelin positive populations in the cortex, striatum and thalamus. The main findings are: 1) The identification of a new reelin population in the cortex during development. Although reelin was described previously during development in the Cajal-Retzius cells, we also founded a new reelin neuronal population in the intermediate/subplate zone. 2) In my work we show the colocalization of reelin and DARPP-32 in the striatum during development and the data obtained suggests that reelin may be involved in the development of striatal connections. 3) We also observed the presence of reelin in the lateral olfactory tract in the neonatal piriform cortex, and the absence of reelin in the pyramidal cells of the piriform cortex, which suggests that reelin is being transported by the axons from the mitral cells, and its possible role in the formation of connections in the layer IA of the piriform cortex. 4) We also characterized the reelin neuronal populations in the thalamus and we found that in the rat brain reelin is not present in the zona limitans intrathalamica, as was described previously in mouse. 5) Finally we provided an in-depth study of reelin in the hindbrain during development, where reelin expression was barely described before. We have found reelin RNA and protein in different nuclei, proliferative areas and in important signaling regions such as the roof plate.