New neurons in the adult brain transiently express molecules related to neuronal development, such as the polysialylated form of neural cell adhesion molecule, or doublecortin (DCX). These molecules are also expressed by a cell population in the rat paleocortex layer II, whose origin, phenotype, and function are not clearly understood. We have classified most of these cells as a new cell type termed tangled cell. Some cells with the morphology of semilunar--pyramidal transitional neurons were also found among this population, as well as some scarce cells resembling semilunar, pyramidal. and fusiform neurons. We have found that none of these cells in layer II express markers of glial cells, mature, inhibitory, or principal neurons. They appear to be in a prolonged immature state, confirmed by the coexpression of DCX, TOAD/Ulip/CRMP-4, A3 subunit of the cyclic nucleotide-gated channel, or phosphorylated cyclic adenosine monophosphate response element--binding protein. Moreover, most of them lack synaptic contacts, are covered by astroglial lamellae, and fail to express cellular activity markers, such as c-Fos or Arc, and N-methyl-d-aspartate or glucocorticoid receptors. We have found that none of these cells appear to be generated during adulthood or early youth and that most of them have been generated during embryonic development, mainly in E15.5.

Spontaneous neural activity is a basic property of the developing brain, which regulates key developmental processes, including migration, neural differentiation and formation and refinement of connections. The mechanisms regulating spontaneous activity are not known. By using transgenic embryos that overexpress BDNF under the control of the nestin promoter, we show here that BDNF controls the emergence and robustness of spontaneous activity in embryonic hippocampal slices. Further, BDNF dramatically increases spontaneous co-active network activity, which is believed to synchronize gene expression and synaptogenesis in vast numbers of neurons. In fact, BDNF raises the spontaneous activity of E18 hippocampal neurons to levels that are typical of postnatal slices.We also show that BDNF overexpression increases the number of synapses at much earlier stages (E18) than those reported previously. Most of these synapses were GABAergic, and GABAergic interneurons showed hypertrophy and a 3-fold increase in GAD expression.Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K + /Cl -KCC2 cotransporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl -potential. Together, results indicate that both the presynaptic and postsynaptic machineries of GABAergic circuits may be essential targets of BDNF actions to control spontaneous activity. The data indicate that BDNF is a potent regulator of spontaneous activity and co-active networks, which is a new level of regulation of neurotrophins. Given that BDNF itself is regulated by neuronal activity, we suggest that BDNF acts as a homeostatic factor controlling the emergence, complexity and networking properties of spontaneous networks.

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The transcription factor Pax 6 is expressed in precursor cells during embryonic CNS development, and it plays an important role in the regulation of cell proliferation and neuronal fate determination. Pax 6-expressing cells are also present in the adult hippocampal dentate gyrus and subventricular zone/rostral migratory stream, regions in which neuronal precursors exist during adult life. In the adult dentate gyrus, precursor cells are located in the innermost portion of the granule cell layer, and Pax 6-expressing nuclei are most abundant in this region. To examine the putative role of Pax 6 in adult hippocampal neurogenesis, we have studied the proliferative activity, distribution, and phenotype of Pax 6-expressing cells by using immunohistochemistry. Our results indicate that Pax 6 is intensely expressed in proliferating precursors of the adult dentate gyrus. Pax 6 is also expressed in nonproliferating cells, which may correspond to resting progenitor cells and to granule neurons in their very early developmental stages, because this transcription factor is strongly down-regulated during granule neuron differentiation. However, a small subpopulation of hilar mature neurons and certain astrocytes of the adult hippocampus also express Pax 6. Although the precise roles of this transcription factor in the adult brain remain to be determined, our findings support the idea that its function in the control of cell proliferation and neuronal fate determination during embryogenesis is also operative in the adult hippocampus. However, the expression of Pax 6 in astrocytes and certain mature neurons may indicate the existence of other roles for this transcription factor in this telencephalic region.