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The response to postnatal stress: amino acids transporters and PKC activity.

It is well known that animals exposed to stressful stimuli during their early life develop different neurological disorders when they become adults. In this study, we evaluated the effect of acute cold stress on gamma-aminobutyric acid (GABA) and L-Serine (L-Ser) transporters in vitro, using the uptake of [(3)H]-GABA and [(3)H]L-Ser by synaptosomes-enriched fractions isolated from rat cerebral cortex during postnatal development. GABA and L-Ser uptake studies in vitro will be used in this investigation as a colateral evidence of changes in the expression of transporters of GABA and L-Ser. We observed that the maximum velocity (V (max)) in L-Ser and GABA uptake after stress session increased in all stages studied. In contrast, K (m) values of L-Ser uptake enhancent in almost age calculated, excluding at PD21 after cold stress during development, at the same time as K (m) (uptake affinity) values of GABA increased in just about age considered but not at PD5 compared with the control group. Finally we investigated the mechanism by which cells regulate the substrate affinity of L-Ser and GABA transporters. We demonstrated a significantly increase in total PKC activity to PD5 from PD21. Pretreatment with PKC inhibitor: staurosporine (SP) led to a restoration of control uptake in several postnatal-days suggesting a relationship between amino acids system and PKC activation. These findings suggest that a single exposure to postnatal cold stress at different periods after birth modifies both GABA and L-Ser transporters and the related increase in total PKC activity could be intracellular events that participate in neuronal plasticity by early life stress, which could be relevant to function of transporters in the adult rat brain.

Hipótesis epigenética de la esquizofrenia: bases moleculares y modelos experimentales / Epigenetic Hypothesis for Schizophrenia: Molecular bases and Experimental Models

Si bien la predisposición a desarrollar esquizofrenia ha sido, en parte, atribuida a un componente genético, la evidencia experimental de los últimos años sugiere que este trastorno puede ser el resultado de una aberración epigenética. De ahí que a las hipótesis hiperdopaminérgica e hipoglutamatérgica, se le sume la hipótesis epigenética de la esquizofrenia. Esta última propone que la fisiopatología de la enfermedad se sostiene en cambios en la expresión génica por una estructura aberrante de la cromatina, más que por cambios en la secuencia del ADN. De los múltiples blancos moleculares propuestos en la etiología de la enfermedad, cobra particular importancia la enzima ácido glutámico descarboxilasa, encargada de sintetizar el ácido γ - amino butírico (GABA), en especial la isoforma de 67 kDa, y la reelina, cuyos genes codificantes parecen estar hipermetilados en pacientes con esquizofrenia cuando se los compara con individuos sanos. Esto determina un menor nivel de expresión de la enzima y niveles disminuidos de GABA, lo que involucra íntimamente a este neurotransmisor en el desarrollo de la esquizofrenia.(AU)

Although the tendency to develop shizophrenia has partly been ascribed to a genetic component, experimental evidence gathered in recent years suggests that this disorder may be the producto of an epigenetic aberration. Hence, the hyperdopaminergic and hupoglutamatergic hypotheses add on the epigenetic hypothesis for shizophrenial. The latter proposes that the physiopathology of schizophrenia stems from changes in the gene expression, into an aberrant structure of the chromatin, rather than from DNA sequence variations. Oif the multiple molecular targets proposed in the etiology of shizophrenia, one which acquires particular significance is the enzyme, glutamic acid decarboxylase, which synthesizes Y-aminobutyric acid (GABA), especially 67-kDa isoform and reelin, whose codifying genes seem to be hypermethylated in patients with schizophrenia, as compared with healthy individuals. This determines a lower level of expression of the enzyme, as well as rduced GABA levels, which evidences the close relationship betweeen this neurotransmissor and the development of schizophrenia.(AU)

Hipótesis epigenética de la esquizofrenia: bases moleculares y modelos experimentales / Epigenetic Hypothesis for Schizophrenia: Molecular bases and Experimental Models

Si bien la predisposición a desarrollar esquizofrenia ha sido, en parte, atribuida a un componente genético, la evidencia experimental de los últimos años sugiere que este trastorno puede ser el resultado de una aberración epigenética. De ahí que a las hipótesis hiperdopaminérgica e hipoglutamatérgica, se le sume la hipótesis epigenética de la esquizofrenia. Esta última propone que la fisiopatología de la enfermedad se sostiene en cambios en la expresión génica por una estructura aberrante de la cromatina, más que por cambios en la secuencia del ADN. De los múltiples blancos moleculares propuestos en la etiología de la enfermedad, cobra particular importancia la enzima ácido glutámico descarboxilasa, encargada de sintetizar el ácido γ - amino butírico (GABA), en especial la isoforma de 67 kDa, y la reelina, cuyos genes codificantes parecen estar hipermetilados en pacientes con esquizofrenia cuando se los compara con individuos sanos. Esto determina un menor nivel de expresión de la enzima y niveles disminuidos de GABA, lo que involucra íntimamente a este neurotransmisor en el desarrollo de la esquizofrenia.

Although the tendency to develop shizophrenia has partly been ascribed to a genetic component, experimental evidence gathered in recent years suggests that this disorder may be the producto of an epigenetic aberration. Hence, the hyperdopaminergic and hupoglutamatergic hypotheses add on the epigenetic hypothesis for shizophrenial. The latter proposes that the physiopathology of schizophrenia stems from changes in the gene expression, into an aberrant structure of the chromatin, rather than from DNA sequence variations. Oif the multiple molecular targets proposed in the etiology of shizophrenia, one which acquires particular significance is the enzyme, glutamic acid decarboxylase, which synthesizes Y-aminobutyric acid (GABA), especially 67-kDa isoform and reelin, whose codifying genes seem to be hypermethylated in patients with schizophrenia, as compared with healthy individuals. This determines a lower level of expression of the enzyme, as well as rduced GABA levels, which evidences the close relationship betweeen this neurotransmissor and the development of schizophrenia.

L-serine and GABA uptake by synaptosomes during postnatal development of rat.

Postnatal development changes in mechanisms of synaptosomal amino acid transport have been studied in rat cerebral cortex. Specific uptake of radiolabeled L-serine was examined and compared with that of radiolabeled GABA using synaptosomes-enriched fractions freshly prepared from cerebral cortex at different postnatal days from the birth to young adulthood. The preparations were incubated with 10 nM of [3H]L-serine and 10 nM of [3H]-GABA in either the presence or absence of NaCl, KCl or choline chloride, at 2 and 30 degrees C, for different periods up to 30 min. The uptake of [3H]l-serine was temperature dependent in synaptosomal fractions prepared from cerebral cortex of rats in postnatal days 5, 7, 13 and 21, but stronger dependence was observed in adult brain, irrespective of the presence of Na+, K+ or choline ions. At all postnatal ages studied, [3H]-GABA uptake showed a high activity in the presence of Na+ ions and at 30 degrees C. The values of Km were 90-489 microM in L-serine uptake. However, in the uptake of GABA the values of Km were 80-150 microM. The highest values of Vmax were obtained at 5 and 21 postnatal days for both transport systems. These results indicate that the uptake of l-serine and GABA are regulated differentially during postnatal development.