Oligodendrocytes are cells that myelinate axons, providing saltatory conduction of action potentials and proper function of the central nervous system. Myelination begins prenatally in the human, and the sequence of oligodendrocyte development and the onset of myelination are not thoroughly investigated. This knowledge is important to better understand human diseases, such as periventricular leukomalacia, one of the leading causes of motor defi cit in premature babies, and demyelinating disorders such as multiple sclerosis (MS). In this review we discuss the spatial and temporal progression of oligodendrocyte lineage characterized by the expression of specifi c markers and transcription factors in the human fetal brain from the early embryonic period (5 gestational weeks, gw) until midgestation (24 gw). Our in vitro evidence indicated that a subpopulation of human oligodendrocytes may have dorsal origin, from cortical radial glia cells, in addition to their ventral telencephalic origin. Furthermore, we demonstrated that the regulation of myelination in the human fetal brain includes positive and negative regulators. Chemokines, such as CXCL1, abundant in proliferative zones during brain development and in regions of remyelination in adult, are discussed in the view of their potential roles in stimulating oligodendrocyte development. Other signals are inhibitory and may include, but are not limited to, polysialic acid modifi cation of the neural cell adhesion molecule on axons. Overall, important differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation exist between human and rodent brains. Those differences may underlie the unique susceptibility of humans to demyelinating diseases, such as MS.

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability.

Background:The neural cell adhesion molecule L1 is important in the developing and adult nervous system. Results: L1 stimulation leads to sumoylation and proteolytic processing of L1 and translocation of a sumoylated transmembrane fragment to the nucleus. Conclusion: Sumoylation and nuclear localization of the L1 fragment are required for L1-dependent functions. Significance: Unraveling the molecular mechanisms underlying L1-activated cellular responses helps understanding L1-linked disorders.

The Ig superfamily adhesion molecule CHL1, the close homolog of the adhesion molecule L1, promotes neurite outgrowth, neuronal migration, and survival in vitro. We tested whether CHL1, similar to its close homolog L1, has a beneficial impact on recovery from spinal cord injury using adult CHL1-deficient (CHL1 Ϫ/Ϫ ) mice and wild-type (CHL1 ϩ/ϩ ) littermates. In contrast to our hypothesis, we found that functional recovery, assessed by locomotor rating and video-based motion analyses, was improved in CHL1 Ϫ/Ϫ mice compared with wild-type mice at 3-6 weeks after compression of the thoracic spinal cord. Better function was associated with enhanced monoaminergic reinnervation of the lumbar spinal cord and altered pattern of posttraumatic synaptic rearrangements around motoneurons. Restricted recovery of wild-type mice was likely related to early and persistent (3-56 d after lesion) upregulation of CHL1 in GFAP-positive astrocytes at the lesion core. In both the intact spinal cord and cultured astrocytes, enhanced expression of CHL1 and GFAP was induced by application of basic fibroblast growth factor, a cytokine involved in the pathophysiology of spinal cord injury. This upregulation was abolished by inhibitors of FGF receptor-dependent extracellular signal-regulated kinase, calcium/calmodulin-dependent kinase, and phosphoinositide-3 kinase signaling pathways. In homogenotypic and heterogenotypic cocultures of neurons and astrocytes, reduced neurite outgrowth was observed only if CHL1 was simultaneously present on both cell types. These findings and novel in vitro evidence for a homophilic CHL1-CHL1 interaction indicate that CHL1 is a glial scar component that restricts posttraumatic axonal growth and remodeling of spinal circuits by homophilic binding mechanisms.

Cortical γ-aminobutyric acid (GABA)ergic interneurons in rodents originate mainly in ventrally positioned ganglionic eminences (GEs), but their origin in primates is still debated. We studied human fetal forebrains during the first half of gestation (5-23 gestational weeks, gw) for the expression of ventral transcription factors, Nkx2.1, Dlx1,2, Lhx6, and Mash1, important for development of neocortical interneurons. In embryonic (5-8 gw) human forebrain, these factors were expressed in the GE but also dorsally in the neocortical ventricular/subventricular zones (VZ/SVZ). Furthermore, their expression was retained in cells of all fetal cortical layers up to midgestation (20 gw). Nkx2.1 continued to be expressed not only in the GE but also in a subpopulation of neocortical interneurons. Moreover, proliferation marker Ki67 revealed that calretinin(+), Mash1(+), and Nkx2.1(+) cells proliferate in the neocortical VZ/SVZ at midgestation. At least some of the Mash1(+) progenitors in the neocortical SVZ could be colabeled with GABA, whereas others were oligodendrocyte progenitors, indicating a link between the 2 lineages. Taken together, these results suggest the existence of several categories of dorsal interneuronal progenitors in the human neocortical VZ/SVZ, in addition to ventrally derived cortical interneurons described in rodents. These human-specific developmental events may underlie human brain's higher complexity and capacity to process information.

The transcription factors Olig1 and Olig2 are closely associated with the development of oligodendrocyte (OL) lineage in the vertebrate nervous system, but little is known about their role in the human developing CNS. To test the hypothesis that they contribute to initial OL specification in humans, we studied the expression of Olig1 and Olig2 in human fetuses at 5-24 gestational weeks (GW). Both transcription factors were present in well outlined regions of the ventral neuroepithelium at 5 GW, several weeks before oligodendrogenesis. Spatial differences in the expression of Olig1 and Olig2 along the neuronal axis suggest that they specify different subpopulations of progenitor cells. Olig1 was distributed rostrally, from the basal forebrain to the hindbrain, whereas Olig2 was also found in the ventral spinal cord. Furthermore, at 5 GW, Olig1 was coexpressed with vimentin, and Olig2 was coexpressed with a neuronal marker, microtubule-associated protein 2. With the progression of development at 15 GW, both proteins were present throughout the spinal cord and the ventricular-subventricular zone of the ganglionic eminences, whereas at midgestation (20 GW), they were also expressed in the telencephalic proliferative zones and the emerging white matter. Double-labeling studies revealed that early OL progenitor cells and radial glia expressed Olig1, whereas Olig2 was localized predominantly in mature OLs and a subset of neural progenitor cells and mature neurons. Thus, Olig1 and Olig2 transcription factors in the human CNS are important not only for differentiation of the OL lineage, but they may also have a role in neural cell specification.

The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.

Oligodendrocytes (OL), cells that myelinate axons in the CNS, differentiate from early to late oligodendrocyte progenitor cells (OPC) to become mature OL. Unlike the case in the rodent brain, myelin formation starts prenatally in the human brain, but the sequence of OL development and the onset of myelination are not well understood. We studied the human fetal forebrain at midgestation (17-23 gestational weeks, g.w.) using OL lineage-specific antibodies and mRNA probes. Early OPC were present in a gradient from the subventricular zone to the cortical plate. Their close apposition to radial glia fibers suggests a possible role of these fibers in OPC migration. Late OPC reached peak density in the subplate layer, whereas multipolar cells with the morphology of mature OL were restricted to the emerging white matter. At 20 g.w., myelinated axons were observed in the diencephalon, but not in the telencephalon, consistent with caudal-to-rostral progression of myelination. Interestingly, in organotypic slice cultures of the same gestational ages, the subventricular zone contained a considerably greater number of the mature OL cells, suggesting the presence of inhibitory signals in vivo. Overall, in addition to considerable similarities with rodents, important differences in temporal and spatial distribution and regulatory signals for OL differentiation exist in the human brain.