Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic gamma-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABA(A)-receptor subunits alpha2 and alpha4. Our data indicate that in the MeCP2 -/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

In contrast to the single sensory surface present in teleost fishes, several spatially segregated subsystems with distinct molecular and functional characteristics define the mammalian olfactory system. However, the evolutionary steps of that transition remain unknown. Here we analyzed the olfactory system of an early diverging tetrapod, the amphibian Xenopus laevis, and report for the first time the existence of two odor-processing streams, sharply segregated in the main olfactory bulb and partially segregated in the olfactory epithelium of pre-metamorphic larvae. A lateral odor-processing stream is formed by microvillous receptor neurons and is characterized by amino acid responses and Gαo/Gαi as probable signal transducers, whereas a medial stream formed by ciliated receptor neurons is characterized by responses to alcohols, aldehydes, and ketones, and Gαolf/cAMP as probable signal transducers. To reveal candidates for the olfactory receptors underlying these two streams, the spatial distribution of 12 genes from four olfactory receptor gene families was determined. Several class II and some class I odorant receptors (ORs) mimic the spatial distribution observed for the medial stream, whereas a trace amine-associated receptor closely parallels the spatial pattern of the lateral odor-processing stream. Other olfactory receptors (some class I odorant receptors and vomeronasal type 1 receptors) and odor responses (to bile acids, amines) were not lateralized, the latter not even in the olfactory bulb, suggesting an incomplete segregation. Thus, the olfactory system of X. laevis exhibits an intermediate stage of segregation and as such appears well suited to investigate the molecular driving forces behind olfactory regionalization.

␣-Neurexins are neuron-specific cell-surface molecules that are essential for the functional organization of presynaptic Ca 2؉ channels and release sites. We have now examined postsynaptic glutamate receptor function in ␣-neurexin knockout (KO) mice by using whole-cell recordings in cultured neocortical slices. Unexpectedly, we find that ␣-neurexins are required for normal activity of N-methyl-D-aspartate (NMDA)-but not ␣-amino-3-hydroxy-5-methyl-4-isoxyzolepropionic acid (AMPA)-type glutamate receptors. In ␣-neurexin-deficient mice, the ratio of NMDA-to AMPAreceptor currents, recorded as evoked synaptic responses, was diminished Ϸ50%. Furthermore, the NMDA-receptor-dependent component of spontaneous synaptic miniature responses was reduced Ϸ50%, whereas the AMPA-receptor-dependent component was unaffected. No alterations in the levels of NMDA-or AMPA-receptor proteins were detected. These results suggest that ␣-neurexins are required to maintain normal postsynaptic NMDAreceptor function. The decrease in NMDA-receptor activity in ␣-neurexin-deficient synapses could be due to a transsynaptic effect on the postsynaptic neuron (i.e., ␣-neurexins on the presynaptic inputs guide postsynaptic NMDA-receptor function) or to a cell-autonomous postsynaptic effect of ␣-neurexins on NMDAreceptor activity. To distinguish between these two possibilities, we cocultured WT GFP-labeled neurons with neocortical slices from ␣-neurexin-deficient or control mice. No difference was found between WT neurons innervated by inputs that contained or lacked ␣-neurexins, indicating that the absence of presynaptic ␣-neurexins alone does not depress postsynaptic NMDA-receptor function. Our data suggest that, in addition to the previously described presynaptic impairments, loss of ␣-neurexins induces postsynaptic changes by a cell-autonomous mechanism.T he physiological properties of excitatory synapses of a set of neurons, or even the same neuron, can differ remarkably (1-4). Multiple pre-and postsynaptic processes differentially regulate the strength of synapses. For example, in cortical synapses, the properties of presynaptic release sites formed by a single neuron can be differentially modulated by the postsynaptic target neuron (5). At least in part, this regulation appears to act on the amount of presynaptic Ca 2ϩ influx that is induced by an action potential. Conversely, postsynaptic glutamate receptors are modulated by synaptic activity (6, 7). Both of the two principal types of synaptic glutamate receptors, N-methyl-Daspartate (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxyzolepropionic acid (AMPA) receptors, undergo such usedependent changes (7-9). The two receptor types are coordinately up-or down-regulated when the total strength of the synaptic inputs into a neuron is held constant during synaptic scaling (9). In contrast, only AMPA receptors are selectively increased during NMDA-receptor-dependent long-term potentiation in the CA1 region of the hippocampus (7). Viewed together, synapses can thus be considered as dynamic units in wh...