Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development, and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA sub-type of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possible other ASDs.

The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.

TheCase o f Poland THE POLITICAL and intellectual leaders of Eastern Europe's revolution of 1989 describe their aim as a "return to Europe." Their overwhelming judgment is that the postwar division of Europe into East and West was artificially imposed by the Soviet Union, at enormous human and economic cost. They underscore the artificiality of the division by referring to their region as East Central Europe (or Middle Europe), rather than Eastern Europe, thereby stressing their countries' place in the mainstream of European history, politics, arts, and economy. The policy dimension of the return to Europe is the creation of political and economic institutions in the style of Western Europe. I In this spirit, these countries are directed toward the creation of multiparty parliamentary democracies and market economies with large private sectors.2 1. The degree of consensus in Eastern Europe in favor of establishing a Western-style market economy certainly exceeds the levels of consensus found in Latin America and other parts of the developing world. In many Latin American countries, such as Argentina, Brazil, and Peru, there are still fundamental battles (even violent war in the case of Peru) about the kind of society and economy to which the nation should aspire. Of course, as the abstract idea of a market economy is put into practice and the pressures of adjustment grow, we will find out whether today's consensus survives. We believe that it will, largely because of the overwhelming attraction of the Western European example.2. Of course, even Western Europe offers a wide array of alternative economic models from which to choose, but in practical terms there is little reason yet for the Eastern European countries to choose among the variants of Western European political economy. Before such choices have to be made, Eastern Europe should work hard to create the common core of market institutions found in all of Western Europe: private ownership protected by a commercial law, a corporate structure for industry, an independent financial system, and so forth. 76 Brookings Papers on Economic Activity, 1:1990With amazing rapidity, the postcommunist politicians of Poland, Czechoslovakia, and Hungary have dropped any support for an economic "third way"-that is, some form of market socialism-and seem intent on moving instead to a full-fledged market economy based on private property.3 So far in 1990, political majorities in East Germany and Hungary have strongly rejected political currents linked to a continuation of socialism.4The intense desire to rejoin the economies of Western Europe reflects both an attraction to the obvious achievements of Western Europe and a revulsion against the failures under communism. The low per capita incomes in Eastern Europe do not fully explain the pervasive sense of frustration in the region. It is one thing to be poor, but it is quite another to have become impoverished needlessly as a result of the failure of the communist system. It is the sense of unnecessary decay, as much as the ...

Kinesin motor proteins transport intracellular cargos throughout cells by hydrolyzing ATP and moving along microtubule tracks. Intramolecular autoinhibitory interactions have been shown for several kinesins in vitro, however, the physiological significance of autoinhibition remains poorly understood. Here, we identified four mutations in the stalk region and motor domain of synaptic vesicle kinesin, UNC-104/KIF1A, that specifically disrupt autoinhibition. These mutations augment both microtubule and cargo vesicle binding in vitro. In vivo, these mutations cause excessive activation of UNC-104, leading to decreased synaptic density, smaller synapses and ectopic localization of synaptic vesicles in the dendrite. We also show that the synaptic vesicle bound small GTPase ARL-8 activates UNC-104 by unlocking the autoinhibition. These results demonstrate that the autoinhibitory mechanism is utilized to regulate the distribution of transport cargoes and is important for synaptogenesis in vivo.