Synapse formation on adult-born hippocampal neurons.

It is now widely accepted that adult neurogenesis plays a fundamental role in hippocampal function. Neurons born in the adult dentate gyrus of the hippocampus undergo a series of events before they fully integrate in the network and eventually become undistinguishable from neurons born during embryogenesis. Adult hippocampal neurogenesis is strongly regulated by neuronal activity and neurotransmitters, and the synaptic integration of adult-born neurons occurs in discrete steps, some of which are very different from perinatal synaptogenesis. Here, we review the current knowledge on the development of the synaptic input and output of neurons born in the adult hippocampus, from the stem/progenitor cell to the fully mature neuron. We also provide insight on the regulation of adult neurogenesis by some neurotransmitters and discuss some specificities of the integration of new neurons in an adult environment. The understanding of the mechanisms regulating the synaptic integration of adult-born neurons is not only crucial for our understanding of brain plasticity, but also provides a framework for the manipulation and monitoring of endogenous adult neurogenesis as well as grafted cells, for potential therapeutic applications.

Learning-induced plasticity in human audition: Objects, time, and space.

The human auditory system is comprised of specialized but interacting anatomic and functional pathways encoding object, spatial, and temporal information. We review how learning-induced plasticity manifests along these pathways and to what extent there are common mechanisms subserving such plasticity. A first series of experiments establishes a temporal hierarchy along which sounds of objects are discriminated along basic to fine-grained categorical boundaries and learned representations. A widespread network of temporal and (pre)frontal brain regions contributes to object discrimination via recursive processing. Learning-induced plasticity typically manifested as repetition suppression within a common set of brain regions. A second series considered how the temporal sequence of sound sources is represented. We show that lateralized responsiveness during the initial encoding phase of pairs of auditory spatial stimuli is critical for their accurate ordered perception. Finally, we consider how spatial representations are formed and modified through training-induced learning. A population-based model of spatial processing is supported wherein temporal and parietal structures interact in the encoding of relative and absolute spatial information over the initial ∼300ms post-stimulus onset. Collectively, these data provide insights into the functional organization of human audition and open directions for new developments in targeted diagnostic and neurorehabilitation strategies.

Altered ligands reveal limited plasticity in the T cell response to a pathogenic epitope.

Experimental leishmaniasis offers a well characterized model of T helper type 1 cell (Th1)-mediated control of infection by an intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells in response to infection and are unable to control parasite dissemination. The early CD4(+) T cell response in these mice is oligoclonal and reflects the expansion of Vbeta4/ Valpha8-bearing T cells in response to a single epitope from the parasite Leishmania homologue of mammalian RACK1 (LACK) antigen. Interleukin 4 (IL-4) generated by these cells is believed to direct the subsequent Th2 response. We used T cells from T cell receptor-transgenic mice expressing such a Vbeta4/Valpha8 receptor to characterize altered peptide ligands with similar affinity for I-Ad. Such altered ligands failed to activate IL-4 production from transgenic LACK-specific T cells or following injection into BALB/c mice. Pretreatment of susceptible mice with altered peptide ligands substantially altered the course of subsequent infection. The ability to confer a healer phenotype on otherwise susceptible mice using altered peptides that differed by a single amino acid suggests limited diversity in the endogenous T cell repertoire recognizing this antigen.

Separate neuronal and glial Na+,K+-ATPase isoforms regulate glucose utilization in response to membrane depolarization and elevated extracellular potassium.

The role of cell type-specific Na+,K+-ATPase isozymes in function-related glucose metabolism was studied using differentiated rat brain cell aggregate cultures. In mixed neuron-glia cultures, glucose utilization, determined by measuring the rate of radiolabeled 2-deoxyglucose accumulation, was markedly stimulated by the voltage-dependent sodium channel agonist veratridine (0.75 micromol/L), as well as by glutamate (100 micromol/L) and the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) (10 micromol/L). Significant stimulation also was elicited by elevated extracellular potassium (12 mmol/L KCl), which was even more pronounced at 30 mmol/L KCl. In neuron-enriched cultures, a similar stimulation of glucose utilization was obtained with veratridine, specific ionotropic glutamate receptor agonists, and 30 mmol/L but not 12 mmol/L KCl. The effects of veratridine, glutamate, and NMDA were blocked by specific antagonists (tetrodotoxin, CNQX, or MK801, respectively). Low concentrations of ouabain (10(-6) mol/L) prevented stimulation by the depolarizing agents but reduced only partially the response to 12 mmol/L KCl. Together with previous data showing cell type-specific expression of Na+,K+-ATPase subunit isoforms in these cultures, the current results support the view that distinct isoforms of Na+,K+-ATPase regulate glucose utilization in neurons in response to membrane depolarization, and in glial cells in response to elevated extracellular potassium.

Increased plasticity of the stiffness of melanoma cells correlates with their acquisition of metastatic properties.

The stiffness of tumor cells varies during cancer progression. In particular, metastatic carcinoma cells analyzed by Atomic Force Microscopy (AFM) appear softer than non-invasive and normal cells. Here we examined by AFM how the stiffness of melanoma cells varies during progression from non-invasive Radial Growth Phase (RGP) to invasive Vertical Growth Phase (VGP) and to metastatic tumors. We show that transformation of melanocytes to RGP and to VGP cells is characterized by decreased cell stiffness. However, further progression to metastatic melanoma is accompanied by increased cell stiffness and the acquisition of higher plasticity by tumor cells, which is manifested by their ability to greatly augment or reduce their stiffness in response to diverse adhesion conditions. We conclude that increased plasticity, rather than decreased stiffness as suggested for other tumor types, is a marker of melanoma malignancy. These findings advise caution about the potential use of AFM for melanoma diagnosis. FROM THE CLINICAL EDITOR: This study investigates the changes to cellular stiffness in metastatic melanoma cells examined via atomic force microscopy. The results demonstrate that increased plasticity is a marker of melanoma malignancy, as opposed to decreased stiffness.

Regulation of microtubule dynamics by the neuronal growth-associated protein SCG10.

Dynamic assembly and disassembly of microtubules is essential for cell division, cell movements, and intracellular transport. In the developing nervous system, microtubule dynamics play a fundamental role during neurite outgrowth, elongation, and branching, but the molecular mechanisms involved are unknown. SCG10 is a neuron-specific protein that is membrane-associated and highly enriched in growth cones. Here we show that SCG10 binds to microtubules, inhibits their assembly, and can induce microtubule disassembly. We also show that SCG10 overexpression enhances neurite outgrowth in a stably transfected neuronal cell line. These data identify SCG10 as a key regulator of neurite extension through regulation of microtubule instability.

'Hearts and bones': the ups and downs of 'plasticity' in stem cell biology.

More than a decade ago, 'plasticity' suddenly became a 'fashionable' topic with overemphasized implications for regenerative medicine. The concept of 'plasticity' is supported by old transplantation work, at least for embryonic cells, and metaplasia is a classic example of plasticity observed in patients. Nevertheless, the publication of a series of papers showing rare conversion of a given cell type into another unrelated cell raised the possibility of using any unaffected tissue to create at will new cells to replace a different failing tissue or organ. This resulted in disingenuous interpretations and a reason not to fund anymore research on embryonic stem cells (ESc). Moreover, many papers on plasticity were difficult to reproduce and thus questioned; raising issues about plasticity as a technical artefact or a consequence of rare spontaneous cells fusion. More recently, reprogramming adult differentiated cells to a pluripotent state (iPS) became possible, and later, one type of differentiated cell could be directly reprogrammed into another (e.g. fibroblasts into neurons) without reverting to pluripotency. Although the latter results from different and more robust experimental protocols, these phenomena also exemplify 'plasticity'. In this review, we want to place 'plasticity' in a historical perspective still taking into account ethical and political implications.

Plasticity in sex allocation in the plant Mercurialis annua is greater for hermaphrodites sampled from dimorphic than from monomorphic populations.

Plants are notoriously variable in gender, ranging in sex allocation from purely male through hermaphrodite to purely female. This variation can have both a genetic and an adaptive plastic component. In gynodioecious species, where females co-occur with hermaphrodites, hermaphrodites tend to shift their allocation towards greater maleness when growing under low-resource conditions, either as a result of hermaphrodites shifting away from an expensive female function, or because of enhanced siring advantages in the presence of females. Similarly, in the androdioecious plant Mercurialis annua, where hermaphrodites co-exist with males, hermaphrodites also tend to enhance their relative male allocation under low-resource conditions. Here, we ask whether this response differs between hermaphrodites that have been evolving in the presence of males, in a situation analogous to that supposed for gynodioecious populations, vs. those that have been evolving in their absence. We grew hermaphrodites of M. annua from populations in which males were either present or absent under different levels of nutrient availability and compared their reaction norms. We found that, overall, hermaphrodites from populations with males tended to be more female than those from populations lacking males. Importantly, hermaphrodites' investment in pollen and seed production was more plastic when they came from populations with males than without them, reducing their pollen production at low resource availability and increasing their seed production at high resource availability. These results are consistent with the hypothesis that plasticity in sex allocation is enhanced in hermaphrodites that have likely been exposed to variation in mating opportunities due to fluctuations in the frequency of co-occurring males.

Insights into neuronal cell metabolism using NMR spectroscopy: uridyl diphosphate N-acetyl-glucosamine as a unique metabolic marker.

Making the switch: Compounds 1 and 2 are used as metabolic markers for NMR detection. When neuronal cells switch to a glycolytic state, an uneven distribution of (13) C in the N-acetyl group results, thus giving a mixture of the metabolites 1 and 2. It is therefore possible to monitor flux through different metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, and the hexosamine biosynthetic pathway, using a single molecule.

Neuronal traits are required for glucose-induced insulin secretion.

The transcriptional repressor RE1 silencer transcription factor (REST) is an important factor that restricts some neuronal traits to neurons. Since these traits are also present in pancreatic beta-cells, we evaluated their role by generating a model of insulin-secreting cells that express REST. The presence of REST led to a decrease in expression of its known target genes, whereas insulin expression and its cellular content were conserved. As a consequence of REST expression, the capacity to secrete insulin in response to mitochondrial fuels, a particularity of mature beta-cells, was impaired. These data provide evidence that REST target genes are required for an appropriate glucose-induced insulin secretion.

Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity.

The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function.

Roles of mGluR5 in synaptic function and plasticity of the mouse thalamocortical pathway.

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the development of cortical sensory maps. However, its precise roles in the synaptic function and plasticity of thalamocortical (TC) connections remain unknown. Here we first show that in mGluR5 knockout (KO) mice bred onto a C57BL6 background cytoarchitectonic differentiation into barrels is missing, but the representations for large whiskers are identifiable as clusters of TC afferents. The altered dendritic morphology of cortical layer IV spiny stellate neurons in mGluR5 KO mice implicates a role for mGluR5 in the dendritic morphogenesis of excitatory neurons. Next, in vivo single-unit recordings of whisker-evoked activity in mGluR5 KO adults demonstrated a preserved topographical organization of the whisker representation, but a significantly diminished temporal discrimination of center to surround whiskers in the responses of individual neurons. To evaluate synaptic function at TC synapses in mGluR5 KO mice, whole-cell voltage-clamp recording was conducted in acute TC brain slices prepared from postnatal day 4-11 mice. At mGluR5 KO TC synapses, N-methyl-D-aspartate (NMDA) currents decayed faster and synaptic strength was more easily reduced, but more difficult to strengthen by Hebbian-type pairing protocols, despite a normal developmental increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated currents and presynaptic function. We have therefore demonstrated that mGluR5 is required for synaptic function/plasticity at TC synapses as barrels are forming, and we propose that these functional alterations at the TC synapse are the basis of the abnormal anatomical and functional development of the somatosensory cortex in the mGluR5 KO mouse.

Neonatal hyperglycemia inhibits angiogenesis and induces inflammation and neuronal degeneration in the retina.

Recent evidence suggests that transient hyperglycemia in extremely low birth weight infants is strongly associated with the occurrence of retinopathy of prematurity (ROP). We propose a new model of Neonatal Hyperglycemia-induced Retinopathy (NHIR) that mimics many aspects of retinopathy of prematurity. Hyperglycemia was induced in newborn rat pups by injection of streptozocine (STZ) at post natal day one (P1). At various time points, animals were assessed for vascular abnormalities, neuronal cell death and accumulation and activation of microglial cells. We here report that streptozotocin induced a rapid and sustained increase of glycemia from P2/3 to P6 without affecting rat pups gain weight or necessitating insulin treatment. Retinal vascular area was significantly reduced in P6 hyperglycemic animals compared to control animals. Hyperglycemia was associated with (i) CCL2 chemokine induction at P6, (ii) a significant recruitment of inflammatory macrophages and an increase in total number of Iba+ macrophages/microglia cells in the inner nuclear layer (INL), and (iii) excessive apoptosis in the INL. NHIR thereby reproduces several aspects of ischemic retinopathies, including ROP and diabetic retinopathies, and might be a useful model to decipher hyperglycemia-induced cellular and molecular mechanisms in the small rodent.

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

Expression and developmental regulation of Ehk-1, a neuronal Elk-like receptor tyrosine kinase in brain.

Protein tyrosine kinases are pivotal in central nervous tissue development and maintenance. Here we focus on the expression of Ehk-1, a novel Elk-related receptor tyrosine kinase. Ehk-1 gene expression is observed in the developing and adult central nervous system and is highly regulated throughout development at both the messenger RNA and protein levels. Three messenger RNA transcripts of 8.5, 5.9 and 5.1 kb are detectable in the rat brain and a variety of splice possibilities have been identified. However, a major protein species of around M(r) 120,000 predominates throughout development. Ehk-1 messenger RNA and protein levels are highest in the first postnatal week. By in situ messenger RNA hybridization the gene is expressed by all neurons of the adult brain, but mostly in the hippocampus, cerebral cortex and large neurons of the deep cerebellar nuclei, as well as the Purkinje and granular cells of the cerebellum. At earlier stages of development, transcripts are most prominent in the periventricular germinal layers of the brain. Immunohistochemistry reveals a pronounced membrane associated protein expression in immature neurons. In the adult animal, peak reactivity was found in the neuropil with sparing of most perikarya. The spatial and temporal pattern of ehk-1 gene expression suggests a role in both the development and maintenance of differentiated neurons of the central nervous system.