The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior.

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.

The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction.

The ubiquitin-proteasome system (UPS) plays a fundamental role in protein degradation in neurons, and there is strong evidence that it fulfills a key role in synaptic transmission. The aim of the present work was to study the implication of one component of the UPS, the HERC1 E3 Ubiquitin Ligase, in motor function and neuromuscular transmission. The tambaleante (tbl) mutant mouse carries a spontaneous mutation in HERC1 E3 Ubiquitin Ligase, provoking an ataxic phenotype that develops in the second month of life. Our results show that motor performance in mutant mice is altered at postnatal day 30, before the cerebellar neurodegeneration takes place. This defect is associated with by: (a) a reduction of the motor end-plate area, (b) less efficient neuromuscular activity in vivo, and (c) an impaired evoked neurotransmitter release. Together, these data suggest that the HERC1 E3 Ubiquitin Ligase is fundamental for normal muscle function and that it is essential for neurotransmitter release at the mouse neuromuscular junction.

Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo.

Oligodendrocytes are the myelin-forming cells in the central nervous system. In the brain, oligodendrocyte precursors arise in multiple restricted foci, distributed along the caudorostral axis of the ventricular neuroepithelium. In chick embryonic hind-, mid- and caudal forebrain, oligodendrocytes have a basoventral origin, while in the rostral fore-brain oligodendrocytes emerge from alar territories (Perez Villegas, E. M., Olivier, C., Spassky, N., Poncet, C., Cochard, P., Zalc, B., Thomas, J. L. and Martinez, S. (1999) Dev. Biol. 216, 98-113). To investigate the respective territories colonized by oligodendrocyte progenitor cells that originate from either the basoventral or alar foci, we have created a series of quail-chick chimeras. Homotopic chimeras demonstrate clearly that, during embryonic development, oligodendrocyte progenitors that emerge from the alar anterior entopeduncular area migrate tangentially to invade the entire telencephalon, whereas those from the basal rhombomeric foci show a restricted rostrocaudal distribution and colonize only their rhombomere of origin. Heterotopic chimeras indicate that differences in the migratory properties of oligodendroglial cells do not depend on their basoventral or alar ventricular origin. Irrespective of their origin (basal or alar), oligodendrocytes migrate only short distances in the hindbrain and long distances in the prosencephalon. Furthermore, we provide evidence that, in the developing chick brain, all telencephalic oligodendrocytes originate from the anterior entopeduncular area and that the prominent role of anterior entopeduncular area in telencephalic oligodendrogenesis is conserved between birds and mammals.

Spatiotemporal development of oligodendrocytes in the embryonic brain.

In the central nervous system (CNS), oligodendrocytes have long been considered to be the last cell type to be generated during development. In rodents, the progenitor cells that give rise to oligodendrocytes have been reported to originate in the subventricular zone. Here, we review recent data demonstrating the existence of oligodendrocyte precursor cells in the ventricular layer of the neural tube that emerge prior to the progenitor stage. Oligodendrocyte precursors arise in restricted foci that are distributed along the rostrocaudal axis of the neural tube, for the most part ventrally. The generation of oligodendrocyte precursor cells occurs either simultaneously with, or follows closely upon the emergence of the first neurons. Experiments with quail-chick chimeras provide evidence that oligodendrocyte progenitors derived from ventricular precursors migrate either tangentially or radially to colonize extensive or segmentally restricted territories of the brain. The choice depends on their site of origin. Finally, we discuss the possibility that oligodendrocytes could be a mosaic population that originates from at least two types of precursor cells.

Single or multiple oligodendroglial lineages: a controversy.

The text books all say oligodendrocytes are the last cell to arise during development. The analysis of the spatio-temporal pattern of expression of plp/dm-20 during embryonic development in both the chick and the mouse provides evidence that the induction of oligodendrocyte occurs much earlier than we thought. In fact, it seems as though these cells must arise nearly simultaneously with neurons and it is just that they do not mature until later. Furthermore, we review the experimental arguments in favor of the existence of at least two, if not more, oligodendrocyte precursor cells: one is defined by the expression of PDGFRalpha, another characterized by expression of plp/dm-20 is independent from PDGF-AA for its proliferation and survival. We then postulate the existence of a third family of yet unknown origin.

Early specification of oligodendrocytes in the chick embryonic brain.

Oligodendrocytes are the myelin-forming cells in the central nervous system of vertebrates. In the rodent embryo, these cells have been shown to emerge from restricted territories of the neuroepithelium. However, a comprehensive view of the development of oligodendroglial populations from their ventricular sources remains to be established. As a first step toward this aim, we have examined in vivo the spatiotemporal emergence of oligodendrocytes in the chick embryonic brain. We have detailed the patterns of expression of three early markers of the oligodendroglial lineage: the plp/dm-20 and PDGFRalpha transcripts and the O4-reactive antigen. During embryonic development, these molecules showed a similar segmental pattern of expression. However, plp/dm-20(+) cells were already observed, in the ventricular layer, at E2.5, i.e., 2 days before the appearance of O4(+) and PDGFRalpha(+) cells, suggesting that oligodendrocyte precursors arise nearly simultaneously with neurons. In the chick embryonic brain, the onset of expression of plp/dm-20 appears therefore to be the earliest event indicative of oligodendroglial specification and we propose, based on the expression of plp/dm-20 transcript, a ventricular map of the foci at which oligodendrocytes originate. In addition, we document the precocious segregation, from E5, of plp/dm-20(+) and PDGFRalpha(+) oligodendroglial cells in the subventricular and mantle layers of the brain.