Expressão de GABA e plasticidade do fenótipo neuroquímico e morfológico de células da Zona Subventricular pós-natal

Abstract

The subventricular zone (SVZ) is proliferative epithelium that continuously gives rise to new neurons in postnatal and adult mammals. The neurons generated in the SVZ migrate through the rostral migratory stream (RMS) where they differentiate in GABAergic interneurons. A characteristic of these neuron precursors is that they start to express GABA while they are still in the SVZ. This fact can lead to the conclusion that at this time they are already commited to the GABAergic phenotype. However, to affirm this one has to show that the origin of GABA in these cells is the same as in mature neurons. One of the most important steps to define GABAergic commitment in neurons is to demonstrate the expression of glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA in mature neurons. Here we show that SVZ cells display low levels of GAD immunocytochemistry and enzyme activity as compared with the olfactory bulb. We also show that these cells are able to synthesize GABA using an alternative source, the putrescine pathway. To test the importance of putrescine made GABA in vivo, we pharmacolgically inhibited putrescine synthesis through DFMO administration. We observed that this treatment lead to an increase of GAD expression in the SVZ and RMS. We also show here that SVZ cells can display phenotypic plasticity. Co-culturing SVZ explants and dorsal telencephalic slices, a spot of glutamatergic neurogenesis, we observed that a subpopulation of SVZ derived neurons differentiated into GABAergic neurons and another into glutamatergic pyramidal neurons. Our working hypothesis is that the putrescine pathway is a mechanism to synthesize GABA without commitment to the GABAergic phenotype. The release of putrescine derived GABA inhibits GAD expression leaving these neuroblasts in an undifferentiated state. The inhibition of putrescine synthesis caused an upregulation of GAD expression which would lead to GABAergic commitment. If we present these neuroblasts with different signals, as those present in the embryonic dorsal telencephalon, they would show plasticity in their phenotypic fate and differentiate into other neurochemical and morphological phenotypes, one of which is the glutamatergic pyramidal neuron.