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Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA ( 3-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. © 2010 Macmillan Publishers Limited. All rights reserved.

Neurodegeneration in Lurcher (Lc) mice results from constitutive activation of delta 2, a subunit of ionotropic glutamate receptors (GluRs) with unknown natural ligands and channel properties. Homo-oligomeric channels of GluR-delta2 with the Lurcher mutation (GluR-delta 2(Lc)) expressed in human embryonic kidney 293 cells showed a doubly rectifying current-voltage relation reminiscent of the block by intracellular polyamines in AMPA/kainate channels. Similarly, the fraction of the total current carried by Ca(2+) was approximately 2-3%, comparable with that found in Ca(2+)-permeable AMPA/kainate channels. Currents through GluR-delta 2(Lc) channels were also potentiated by extracellular Ca(2+) in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca(2+). We examined the functional role of the Q/R site in GluR-delta 2(Lc) by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR-delta 2(Lc)(R) channels showed no voltage-dependent block by intracellular polyamines and were nominally impermeable to Ca(2+). The potentiation by Ca(2+), however, remained intact. Hence, GluR-delta 2(Lc) channels are functionally similar to the AMPA/kainate receptor channels, consistent with the high-sequence identity shared by these subunits within the channel-lining M2 and M3 segments. Furthermore, potentiation by Ca(2+) and a permeability to Ca(2+) comparable with that of AMPA/kainate receptors provide a possible cause for cell death in Lurcher mice and may contribute to cerebellar long-term depression under physiological conditions.

The growth of the human gastric cancer cell line HGT-1 is regulated by a gastrin-like peptide through an autocrine process. In order to analyse the mechanism of action of this peptide, a study at different steps of the cell cycle was considered; so, a blocking of this cell line by thymidine or hydroxy-urea was studied by cytofluorimetry. In normal growth conditions in 10% FCS medium, 57% of the cells were in G0/G1 phase and 31% in S phase. A treatment with 2 mM hydroxy-urea followed by 4 hours in 10% FCS medium led to 85% of the cells in S phase. By successive treatments with thymidine and hydroxy-urea followed by 1 hour in 10% FCS medium, 2 peaks of S phase corresponding to 86% of the cells were observed; after 24 hours, cells were distributed as found for the unconfluent cell line, whatever the treatment. On the other hand, the thymidine kinase activity of unconfluent cells which was relatively elevated as compared to other cell lines (278 mU/mg protein), was increased by synchronisation with hydroxyurea followed by 1 hour in 10% SVF medium (338 mU/mg protein); after 8 hours in 10% FCS medium, this activity decreased at the value observed for cells treated with thymidine followed by 1 hour in 10% FCS medium (214 mU/mg protein). In conclusion, a synchronisation either by thymidine or by hydroxy-urea, led to a blocking of the HGT-1 cell line at different steps of the cell cycle, leading to a better knowledge of its autocrine growth regulation.