Continuous neuronal integration in the cerebral cortex of rodents and humans

Resumen

The neuronal plasticity is the ability of the nervous system to make adaptive functional changes, during development and adulthood. It is referred to all types of changes that modify the shape and structure of neurons and glial cells in the central nervous system (CNS). Among the different levels of plasticity occurring in the adult brain, the neurogenesis is a type of brain plasticity, which involves continuous production and incorporation of new neurons into functional neuronal networks. In the adult mammalian brain, new neurons are traditionally generated in two “canonical neurogenic niches”: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. In addition, different forms of neurogenesis have been also described in the so named “non-canonical” neurogenic niches. Recently, attention has been focused on a form of neurogenesis occurring in the mature CNS, which involves immature neurons not recently generated. The majority of these cells are born during embryonic development, but nevertheless remain in an undifferentiated state until adulthood. In rodents, many of these neurons are located in the layer II of the PCX. By contrast, in mammals with more complex cerebral cortices, including humans, they have a more widespread distribution throughout the neocortex. In order to deepen in the knowledge of these immature neurons, in the present thesis I will focus in the mechanisms that underlie the final stages of development of these immature cells and the factors that promote their differentiation and integration in brain circuits, as well as in the involvement of the plasticity-related molecule PSA-NCAM in these processes. First, I have evaluated the effects of dopamine on the differentiation of immature neurons of the adult rat PCX, studying the expression of dopamine D2 receptors (D2r) in this region and the relationship between dopaminergic fibers and immature neurons (defined by PSA-NCAM expression). In addition, I have analyzed the density of immature neurons after chronic treatments with an antagonist and an agonist of D2r: haloperidol and PPHT, respectively. Then, I have explored the impact of PSA depletion by an intracranial injection of the enzyme EndoN, in a transgenic mouse model (DCX-CreERT2 / Flox-EGFP) to understand the role of this molecule in the differentiation of the immature neurons of the PCX. Finally, I have studied the distribution, morphology and phenotype of these immature neurons in the human cerebral cortex layer II using surgical samples from epileptic patients and post-mortem brain tissue. The data gathered in this thesis, indicate a prominent role of DA, through D2r and PSA-NCAM, on the regulation of the final steps of development of immature neurons in the adult rat PCX layer II. Moreover, I have demonstrated that the depletion of PSA promotes the entry into the final stages of development of these immature neurons. Therefore, PSA-NCAM, through its anti-adhesive and insulating properties, seems to have a key role in the regulation of the mechanism underlaying the maturation of these immature neurons. Finally, the results obtained in this thesis have provided, for the first time, direct evidence for the presence of immature neurons in the human brain, specifically in the layer II of the cerebral cortex, which share many features with those found in the rodent PCX.