The "glutamatergic" granule cells of the dentate gyrus transiently express a GABAergic phenotype when a state of hyperexcitability is induced in the adult rat. Consequently, granule cell (GC) activation provokes monosynaptic GABAergic responses in their targets of area CA3. Because GABA exerts a trophic action on neonatal CA3 and mossy fibers (MF) constitute its main input, we hypothesized that the GABAergic phenotype of the MF could also be transiently expressed early in life. We addressed this possibility with a multidisciplinary approach. Electrophysiological recordings in developing rats revealed that, until day 22-23 of age, glutamate receptor antagonists block the excitatory response evoked in pyramidal cells by GCs, isolating a fast metabotropic glutamate receptor-sensitive GABAergic response. In a clear-cut manner from day 23-24 of age, GC activation in the presence of glutamatergic antagonists was unable to evoke synaptic responses in CA3. Immunohistological experiments showed the presence of GABA and GAD67 (glutamate decarboxylase 67 kDa isoform) in the developing GCs and their MF, and, using reverse transcription-PCR, we confirmed the expression of vesicular GABA transporter mRNA in the developing dentate gyrus and its downregulation in the adult. The GABAergic markers were upregulated and MF inhibitory transmission reappeared when hyperexcitability was induced in adult rats. Our data evidence for the first time a developmental and activity-dependent regulation of the complex phenotype of the GC. At early ages, the GABAergic input from the MF may add to the interneuronal input to CA3 to foster development, and, in the adult, it can possibly protect the system from enhanced excitability.

The pattern of occludin distribution is present from the neonatal age. Claudins-7 and -8 are up-regulated after birth. Each tubular segment expresses a peculiar set of claudins that might be responsible for the permeability properties of their TJs.

Cuerpo: diferencia sexual y género

Certain neurons choose the neurotransmitter they use in an activity-dependent manner, and trophic factors are involved in this phenotypic differentiation during development. Developing hippocampal granule cells (GCs) constitutively express the markers of the glutamatergic and GABAergic phenotypes, but when development is completed, the GABAergic phenotype shuts off. With electrophysiological, single-cell reverse transcription-PCR and immunohistological techniques, we show here that short-term (24 h) cultures of fully differentiated adult glutamatergic GCs, which express glutamate, VGlut-1 (vesicular glutamate transporter) mRNA, calbindin, and dynorphin mRNA, can be induced to reexpress the GABAergic markers GABA, GAD 67 (glutamate decarboxylase 67 kDa isoform), and VGAT (vesicular GABA transporter) mRNA, by sustained synaptic or direct activation of glutamate receptors and by activation of TrkB (tyrosine receptor kinase B) receptors, with brain-derived neurotrophic factor (BDNF) (30 min). The expression of the GABAergic markers was prevented by the blockade of glutamate receptors and sodium or calcium channels, and by inhibitors of protein kinases and protein synthesis. In hippocampal slices of epileptic rats and in BDNF-treated slices from naive rats, we confirmed the appearance of monosynaptic GABA A receptor-mediated responses to GC stimulation, in the presence of glutamate receptors blockers. Accordingly, GC cultures prepared from these slices showed the coexpression of the glutamatergic and GABAergic markers. Our results demonstrate that the neurotransmitter choice of the GCs, which are unique in terms of their continuing birth and death throughout life, depends on programmed and environmental factors, and this process is neither limited by a critical developmental period nor restricted by their insertion in their natural network.