Sexual differentiation of the vertebrate brain: principles and mechanisms

A wide variety of sexual dimorphisms, structural differences between the sexes, have been described in the brains of many vertebrate species, including humans. In animal models of neural sexual dimorphism, gonadal steroid hormones, specifically androgens, play a crucial role in engendering these differences by masculinizing the nervous system of males. Usually, the androgen must act early in life, often during the fetal period to masculinize the nervous system and behavior. However, there are a few examples of androgen, in adulthood, masculinizing both the structure of the nervous system and behavior. In the modal pattern, androgens are required both during development and adulthood to fully masculinize brain structure and behavior. In rodent models of neural sexual dimorphism, it is often the aromatized metabolites of androgen, i.e., estrogens, which interact with estrogen receptors to masculinize the brain, but there is little evidence that aromatized metabolites of androgen play this role in primates, including humans. There are other animal models where androgens themselves masculinize the nervous system through interaction with androgen receptors. In the course of masculinizing the nervous system, steroids can affect a wide variety of cellular mechanisms, including neurogenesis, cell death, cell migration, synapse formation, synapse elimination, and cell differentiation. In animal models, there are no known examples where only a single neural center displays sexual dimorphism. Rather, each case of sexual dimorphism seems to be part of a distributed network of sexually dimorphic neuronal populations which normally interact with each other. Finally, there is ample evidence of sexual dimorphism in the human brain, as sex differences in behavior would require, but there has not yet been any definitive proof that steroids acting early in development directly masculinize the human brain.     

Formation of the neuromuscular junction: molecules and mechanisms

The vertebrate skeletal neuromuscular junction is the site at which motor neurons communicate with their target muscle fibers. At this synapse, as at synapses throughout the nervous system, efficient and appropriate communication requires the formation and precise alignment of specializations for transmitter release in the axon terminal with those for transmitter detection in the postsynaptic cell. Classical developmental studies demonstrate that synapse formation at the neuromuscular junction is a mutually inductive event; neurons induce postsynaptic differentiation in muscle cells and myofibers induce presynaptic differentiation in motor axon terminals. More recent experiments indicate that Schwann cells, which cap axon terminals, also play an active role in the formation and maintenance of the neuromuscular junction. Here, we review recent advances in the identification of molecules mediating such inductive interactions and the mechanisms by which they produce their effects. Although our discussion concerns events at developing neuromuscular junctions, it seems likely that similar molecules and mechanisms may act at neuron-neuron synapses in the peripheral as well as the central nervous system.     

Lesion-induced plasticity of central neurons: sprouting of single fibres in the rat hippocampus after unilateral entorhinal cortex lesion

In response to a central nervous system trauma surviving neurons reorganize their connections and form new synapses that replace those lost by the lesion. A well established in vivo system for the analysis of this lesion-induced plasticity is the reorganization of the fascia dentata following unilateral entorhinal cortex lesions in rats. After general considerations of neuronal reorganization following a central nervous system trauma, this review focuses on the sprouting of single fibres in the rat hippocampus after entorhinal lesion and the molecular factors which may regulate this process. First, the connectivity of the fascia dentata in control animals is reviewed and previously unknown commissural fibers to the outer molecular layer and entorhinal fibres to the inner molecular layer are characterized. Second, sprouting of commissural and crossed entorhinal fibres after entorhinal cortex lesion is described. Single fibres sprout by forming additional collaterals, axonal extensions, boutons, and tangle-like axon formations. It is pointed out that the sprouting after entorhinal lesion mainly involves unlesioned fibre systems terminating within the layer of fibre degeneration and is therefore layer-specific. Third, molecular changes associated with axonal growth and synapse formation are considered. In this context, the role of adhesion molecules, glial cells, and neurotrophic factors for the sprouting process are discussed. Finally, an involvement of sprouting processes in the formation of neuritic plaques in Alzheimer's disease is reviewed and discussed with regard to the axonal tangle-like formations observed after entorhinal cortex lesion.     

Axon withdrawal during synapse elimination at the neuromuscular junction is accompanied by disassembly of the postsynaptic specialization and withdrawal of Schwann cell processes

Nerve terminal withdrawal is accompanied by a loss of acetylcholine receptors (AChRs) at corresponding postsynaptic sites during the process of synapse elimination at developing () and reinnervated adult () neuromuscular junctions. Aside from AChR and nerve terminal loss, however, the molecular and cellular alterations that occur at sites of elimination are unknown. To gain a better understanding of the cascade of events that leads to the disassembly of synaptic sites during the synapse elimination process, we surveyed the distribution of molecular elements of the postsynaptic specialization, the basal lamina, and supporting Schwann cells during the process of synapse elimination that occurs after reinnervation. In addition, quantitative techniques were used to determine the temporal order of disappearance of molecules that were lost relative to the loss of postsynaptic AChRs. We found that the dismantling of the postsynaptic specialization was inhomogeneous, with evidence of rapid dissolution of some aspects of the postsynaptic apparatus and slower loss of others. We also observed a loss of Schwann cell processes from sites of synapse elimination, with a time course similar to that seen for nerve terminal retraction. In contrast, all of the extracellular markers that we examined were lost slowly from sites of synapse loss. We therefore conclude that the synapse elimination process is synapse-wide, removing not only nerve terminals but also Schwann cells and many aspects of the postsynaptic apparatus. The disassembly occurs in a stereotyped sequence with some synaptic elements appearing much more stable than others.     

Consequences of cocaine addiction during pregnancy on the development in the child

Cocaine facilitates neurotransmitter release from the central nervous system, decreases their re-uptake at the synapse junction level and increases their blood level due to receptors blockade. During pregnancy cocaine inhibits uterine adrenergic beta receptors and easily crosses the placenta, the main obstetrical consequences of overstimulation of the noradrenergic system being miscarriage, retroplacental haematoma, ruptured uterus, short and premature labour. Fetal and neonatal consequences resulting from both a decreased uterine blood flow and a direct effect of cocaine on fetal development can be severe. Decreased uterine blood flow lowers oxygen and nutriment transport which in turn can induce intra-uterine growth retardation. The direct effect of cocaine on the fetus is responsible for an increased catecholamine plasma concentration leading to vasoconstriction episodes, increased heart rate and blood pressure, and subsequent oxygen requirement. Several malformations have been reported, sometimes severe (involving central nervous system, heart, digestive tract, urinary tract and bone) that are mainly due to fetal circulation failure. Cocaine can also directly alter brain development because of neuronal mistargeting within the cerebral cortex.     

Passover: a gene required for synaptic connectivity in the giant fiber system of Drosophila

Passover (Pas) flies fail to jump in response to a light-off stimulus. The mutation disrupts specific synapses of the giant fibers (GFs), command neurons for this response. Pas was cloned from a P element-induced allele. The cDNA encodes a putative membrane protein of 361 amino acids. Null, hypomorphic, and dominant alleles were sequenced. In the adult central nervous system, and in the pupa during GF synapse formation, Pas is consistently expressed in the GF and in a large thoracic cell in the location of its postsynaptic targets. Pas establishes a new gene family. The Drosophila ogre protein, required for postembryonic neuroblast development, is 47% identical; the C. elegans Unc-7 protein, which when mutated alters the connectivity of a few neurons, is 33% identical.     

Spontaneous and induced remyelination in multiple sclerosis and the Theiler's virus model of central nervous system demyelination

Remyelination in the central nervous system, originally thought to occur rarely, if ever, is now an established phenomena in multiple sclerosis patients. However, the extent of myelin repair is incomplete and limited. Experimental models of central nervous system demyelination provide an opportunity to study the cellular and molecular events involved in remyelination. These models may provide some clue to why remyelination in multiple sclerosis is incomplete as well as suggest potential methods to stimulate central nervous system repair. In this review we examine the morphological aspects of central nervous system remyelination and discuss both spontaneous and induced remyelination in multiple sclerosis and experimental models of central nervous system demyelination. We give special emphasis to the Theiler's virus model of central nervous system demyelination and its usefulness to identify therapeutic agents to promote remyelination. The role of immunoglobulins in promoting remyelination in both the Theiler's model system and in multiple sclerosis is discussed. Finally, we examine the potential physiological role of demyelination and remyelination and its relationship with clinical manifestations of central nervous system disease.     

Ultrasound evaluation of the fetal central nervous system

Evaluation of the fetal central nervous system is an integral part of any obstetric examination. Critical to the diagnosis of central nervous system abnormalities is a basic understanding of the normal fetal anatomy. Anatomic features of a normal ultrasound examination of the fetal central nervous system are discussed. In addition, the sonographic findings associated with a variety of major central nervous system anomalies are reviewed.     

Phospholipase cbeta4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum

Elimination of excess climbing fiber (CF)-Purkinje cell synapses during cerebellar development involves a signaling pathway that includes type 1 metabotropic glutamate receptor, Galphaq, and the gamma isoform of protein kinase C. To identify phospholipase C (PLC) isoforms involved in this process, we generated mice deficient in PLCbeta4, one of two major isoforms expressed in Purkinje cells. PLCbeta4 mutant mice are viable but exhibit locomotor ataxia. Their cerebellar histology, parallel fiber synapse formation, and basic electrophysiology appear normal. However, developmental elimination of multiple CF innervation clearly is impaired in the rostral portion of the cerebellar vermis, in which PLCbeta4 mRNA is predominantly expressed. By contrast, CF synapse elimination is normal in the caudal cerebellum, in which low levels of PLCbeta4 mRNA but reciprocally high levels of PLCbeta3 mRNA are found. These results indicate that PLCbeta4 transduces signals that are required for CF synapse elimination in the rostral cerebellum.     

Cadherin-6 in the developing mouse brain: expression along restricted connection systems and synaptic localization suggest a potential role in neuronal circuitry

Multiple subtypes of the cadherin homophilic cell-cell adhesion molecule are expressed differentially in developing and mature brains, each being expressed in restricted neuronal groups. Cadherin-6 (cad6) is one of such cadherins. Recent studies of cad6 mRNA expression in the postnatal mouse forebrain showed that it occurs in neurons constituting a specific subset of thalamocortical connections. Here we analyzed the localization of cad6 mRNA as well as its protein in the entire central nervous system and also in cranial ganglia of mice at late embryonic to postnatal stages. Our results showed that cad6 is expressed by a limited population of neurons or their precursors, which are synaptically connected to one another, throughout the perinatal stages, and that this expression delineates restricted neuronal circuits from the central to peripheral nervous systems, which include subpathways of the auditory, somatosensory, solitary, vestibular, and olivocerebellar systems. cad6 proteins were detected in these cad6 mRNA-positive neurons on the surface of their cell bodies or dendrites as well as in the cytoplasm. Confocal microscopic analysis revealed that the cad6 protein distribution overlapped that of synaptotagmin in synapse forming areas, suggesting that homotypic cad6 interactions are involved in synaptic connections between neurons expressing this protein. These findings support the idea that cadherin-mediated cell-cell adhesions take part in specific interneuronal connections.     

Experimental down-regulation of the NMDA channel associated with synapse pruning

The N-methyl-D-aspartate (NMDA) receptor has been implicated in activity-dependent synapse stabilization, but its role as a detector of correlated activity during development is debated. In the amphibian retinotectal system, synaptic sorting and stabilization occur throughout larval life, and map refinement is dependent on continuous NMDA receptor function. Moreover, tadpole tecta chronically treated with NMDA selectively fail to maintain retinal synapses wherever their activity correlations are lowest. To determine whether this synapse elimination is associated with a specific down-regulation of NMDA receptor function, whole cell voltage-clamp recordings were made from single neurons in tectal slices. After chronic NMDA treatment, decreases in the magnitude of NMDA currents were detected in glutamatergic synaptic currents, in agonist-evoked currents, and in single-channel currents activated by NMDA. The results suggest that the efficacy of NMDA receptors on tectal neurons determines the amount of correlation required to stabilize sets of tectal inputs during formation of the retinotectal projection.     

Integrin-associated protein is a ligand for the P84 neural adhesion molecule

P84 (also known as SHPS-1, BIT, and SIRP) is a heterophilic adhesive membrane protein involved in receptor tyrosine kinase signaling that is found at synapses in the mammalian central nervous system and in non-neural tissues. We have identified a binding partner for P84 using an expression cloning strategy. Here we report that integrin-associated protein (IAP/CD47) is a predominant binding partner of P84. Immunohistochemistry reveals a virtually identical distribution of P84 and IAP in a variety of adult brain regions. Because IAP has been implicated in cell signaling in cells of the immune system, P84 and IAP represent a heterophilic binding pair that is likely to be involved in bi-directional signaling at the synapse and in other tissues.     

Ophthalmoplegia-ataxia-areflexia in pediatrics. Three new patients and review of the literature

OBJECTIVE: The objective of this study was to investigate if pediatric patients with benign brainstem encephalitis (Bickerstaff Syndrome) or with Miller-Fisher Syndrome are the extremes of the same nosological entity which, in adults, has been named ophalmoplegia-ataxia-areflexia syndrome. PATIENTS AND METHODS: The subjects included in the study were three patients of our institution and 24 patients found in the revision of the English and Spanish pediatric literature who fulfilled the diagnostic criteria of ophtalmoplegia-ataxia-areflexia syndrome. The topographical location of the lesion in the nervous system was based on previously established criteria by using clinical and complementary studies. RESULTS: Of the 27 patients included in the study we were able to reach an accurate topographical diagnosis in 9. None had an exclusive involvement of the peripheral nervous system, (6) had exclusively central nervous system involvement and 2 showed involvement of both system. In 12, the topographical location of the lesion could be only ascertained as probable; 3 of them in the peripheral nervous system, 2 in the central nervous system and mixed involvement in 7. In the remaining 7 patients there were insufficient clinical data to allow topographical classification. CONCLUSIONS: The ophtalmoplegia-ataxia-areflexia syndrome can also be found in pediatric patients. The lesion in the majority of patients in this age group is located in the central nervous system, either alone or combined with peripheral nervous system involvement.     

Pharmacokinetics of antisense analogues in the central nervous system

A thorough evaluation of the pharmacokinetical properties of oligodeoxyribonucleotides (ODN) is a first step towards their rational application as gene expression blockers in the central nervous system (CNS). In this paper we present our own data, as well as those of other authors, on tissue distribution, stability, retention and cellular uptake of phosphodiester, phosphorothioate, and end-capped analogues of ODN introduced into the CNS. ODN are easily distributed within nervous tissue, and their tissue penetration depends on anatomical conditions. Retention of radioactivity delivered with ODN within nervous tissue is higher for phosphodiesters than for phosphorothioates. On the other hand, the tissue stability of phosphorothioates is substantially greater than the tissue stability of phosphodiesters as well as that of end-capped ODN. If the elimination process of ODN is also due to their degradation, it is apparently accomplished by endonucleases, because the recovery of end-capped ODN (resistant to exonucleases) was similar to unprotected phosphodiesters. The uptake of ODN by nerve cells is rather poor, although we have shown that phosphorothioates at least can be internalized by nerve cells in vivo. ODN are metabolized by nerve cells, which results in the formation of unidentified molecules of higher molecular weight than ODN themselves.     

Primary lymphoma of the central nervous system. Review of etiological factors

INTRODUCTION: The primary lymphoma of the central nervous system are between 1 to 2% of all the brain tumors. The most important risk factor for the development of this kind of lesions is both acquired and congenital immunologic deficiency. METHODS AND RESULTS: In this paper we'll try to study the 13 cases of primary lymphomas of the central nervous system from etiological, epidemiological, clinic, diagnostic, therapeutic and outcome point of view. CONCLUSION: Besides we will discuss the bibliography founded paying special attention to diagnostic and therapeutic features.     

Causes of recurrence after laparoscopic hernioplasty. A multicenter study

The neurocutaneous disorders frequently involve the central nervous system. This is the second in a pair of articles describing and illustrating the radiological appearances of the central nervous system manifestations of these disorders, this article looking at tuberous sclerosis, von Hippel-Lindau disease and Sturge-Weber syndrome.