Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

GABAA receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABAA receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABAA receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABAA receptor subunit genes revealed the role of α subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABAA receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltage-independent K+ conductances, and upregulation of GABAA receptors in interneurons that are not affected directly by the mutation. Deletion of the α1 subunit gene leads to complete loss of GABAA receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of α1% mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABAA receptors are required for long-term maintenance of GABAergic synapses in Purkinje cell

Molecular and functional heterogeneity of GABAergic synapses

Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABAA receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABAA receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABAA receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapse

La stampa a Perugia nel Rinascimento

The art of printing with movable type made its appearance in Perugia -then as now, the heart of Italy- in 1471, when the city was under the sway of Braccio Baglioni. Perugia was home to an important university which had been attracting students from all over Europe for more than a century. They found hospitality in two colleges, of which the ‘Sapienza Vecchia’, in particular, was accustomed to accommodating students from abroad. The colleges were themselves instrumental in assisting the work of the earliest printers, all of them foreigners; their enterprise flourished for about fifteen years before strong competition from larger printing centres, notably Venice, took control of the Perugian book market. A second phase in local book production started at the turn of the century under the aegis of two major players, the Cartolari family and Bianchino dal Leone. The history of the book in Perugia is characterized by a quality and originality which is not reflected in the modest quantities produced there, and the major bibliographers have always taken an interest in it. All that and more can be found in this book, the outcome of lengthy research based on detailed analysis of all known editions and archival documents, including a number of new discoveries