Inactivation of calcium-binding protein genes induces 160 Hz oscillations in the cerebellar cortex of alert mice.
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Oscillations in neuronal populations may either be imposed by intrinsically oscillating pacemakers neurons or emerge from specific attributes of a distributed network of connected neurons. Calretinin and calbindin are two calcium-binding proteins involved in the shaping of intraneuronal Ca2+ fluxes. However, although their physiological function has been studied extensively at the level of a single neuron, little is known about their role at the network level. Here we found that null mutations of genes encoding calretinin or calbindin induce 160 Hz local field potential oscillations in the cerebellar cortex of alert mice. These oscillations reached maximum amplitude just beneath the Purkinje cell bodies and are reinforced in the cerebellum of mice deficient in both calretinin and calbindin. Purkinje cells fired simple spikes phase locked to the oscillations and synchronized along the parallel fiber axis. The oscillations reversibly disappeared when gap junctions or either GABA(A) or NMDA receptors were blocked. Cutaneous stimulation of the whisker region transiently suppressed the oscillations. However, the intrinsic somatic excitability of Purkinje cells recorded in slice preparation was not significantly altered in mutant mice. Functionally, these results suggest that 160 Hz oscillation emerges from a network mechanism combining synchronization of Purkinje cell assemblies through parallel fiber excitation and the network of coupled interneurons of the molecular layer. These findings demonstrate that subtle genetically induced modifications of Ca2+ homeostasis in specific neuron types can alter the observed dynamics of the global network. (+info)
Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.
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A conspicuous feature of cortical organization is the wide diversity of inhibitory interneurons; their differential computational functions remain unclear. Here we propose a local cortical circuit in which three major subtypes of interneurons play distinct roles. In a model designed for spatial working memory, stimulus tuning of persistent activity arises from the concerted action of widespread inhibition mediated by perisoma-targeting (parvalbumin-containing) interneurons and localized disinhibition of pyramidal cells via interneuron-targeting (calretinin-containing) interneurons. Moreover, resistance against distracting stimuli (a fundamental property of working memory) is dynamically controlled by dendrite-targeting (calbindin-containing) interneurons. The experimental observation of inverted tuning curves of monkey prefrontal neurons recorded during working memory supports a key model prediction. This work suggests a framework for understanding the division of labor and cooperation among different inhibitory cell types in a recurrent cortical circuit. (+info)
Non-neoplastic granulosa cells within ovarian vascular channels: a rare potential diagnostic pitfall.
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AIMS: To describe six cases seen in consultation in which artefactual vascular involvement within the ovary by benign granulosa cells caused diagnostic confusion. METHODS/RESULTS: In five cases, the initial favoured diagnoses of the submitting pathologists were metastatic carcinoma (three cases) and immature neural elements within a teratoma (two cases). In two cases, the ovary contained a benign cystic teratoma (one with struma ovarii), in two cases endometriosis, in one case follicular cysts, and in the other no pathological lesion was present. In all cases, several small ovarian vascular channels contained cohesive groups of cells with mildly atypical nuclei and cytoplasm, which varied from scant to abundant and eosinophilic. In four cases, mitotic figures were identified. The cells were morphologically consistent with benign granulosa cells and were associated in four cases with a nearby follicle lined by similar cells. There was no evidence of a mass lesion, grossly or histologically, to suggest a granulosa cell tumour. The nature of the cells was confirmed using immunohistochemistry for alpha inhibin and calretinin in one case. CONCLUSIONS: This phenomenon is probably an artefact secondary to surgical trauma or sectioning within the laboratory; alternatively, it could be related to ovulation. It is important that this benign process is not misinterpreted as cancer, either primary or metastatic, which may prompt inappropriate treatment or investigations that are not needed. (+info)
Spatiotemporal patterning of IP3-mediated Ca2+ signals in Xenopus oocytes by Ca2+-binding proteins.
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Ca(2+)-binding proteins (CaBPs) are expressed in a highly specific manner across many different cell types, yet the physiological basis underlying their selective distribution patterns remains unclear. We used confocal line-scan microscopy together with photo-release of IP(3) in Xenopus oocytes to investigate the actions of mobile cytosolic CaBPs on the spatiotemporal properties of IP(3)-evoked Ca(2+) signals. Parvalbumin (PV), a CaBP with slow Ca(2+)-binding kinetics, shortened the duration of IP(3)-evoked Ca(2+) signals and 'balkanized' global responses into discrete localized events (puffs). In contrast, calretinin (CR), a presumed fast buffer, prolonged Ca(2+) responses and promoted 'globalization' of spatially uniform Ca(2+) signals at high [IP(3)]. Oocytes loaded with CR or PV showed Ca(2+) puffs following photolysis flashes that were subthreshold in controls, and the spatiotemporal properties of these localized events were differentially modulated by PV and CR. In comparison to results we previously obtained with exogenous Ca(2+) buffers, PV closely mimicked the actions of the slow buffer EGTA, whereas CR showed important differences from the fast buffer BAPTA. Most notably, puffs were never observed after loading BAPTA, and this exogenous buffer did not show the marked sensitization of IP(3) action evident with CR. The ability of Ca(2+) buffers and CaBPs with differing kinetics to fine-tune both global and local intracellular Ca(2+) signals is likely to have significant physiological implications. (+info)
Early expression of sodium channel transcripts and sodium current by cajal-retzius cells in the preplate of the embryonic mouse neocortex.
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In mouse, the first neurons are generated at embryonic day (E) 12 and form the preplate (PP), which contains a mix of future marginal zone cells, including Cajal-Retzius cells, and subplate cells. To detect developmental changes in channel populations in these earliest-generated neurons of the cerebral cortex, we studied the electrophysiological properties of proliferative cells of the ventricular zone and postmitotic neurons of the PP at E12 and E13, using whole-cell patch-clamp recordings. We found an inward sodium current in 55% of PP cells. To determine whether sodium currents occur in a specific cell type, we stained recorded cells with an antibody for calretinin, a calcium-binding protein found specifically in Cajal-Retzius cells. All calretinin-positive cells had sodium currents, although so did some calretinin-negative cells. To correlate the Na current expression to Na channel gene expression with the Cajal-Retzius cell phenotype, we performed single-cell reverse transcription-PCR on patch-clamp recorded cells to detect expression of the Cajal-Retzius cell marker reelin and the Na channel isoforms SCN 1, 2, and 3. These results showed that virtually all Cajal-Retzius cells (97%), as judged by reelin expression, express the SCN transcript identified as the SCN3 isoform. Of these, 41% presented a functional Na current. There is, however, a substantial SCN-positive population in the PP (27% of SCN-positive cells) that does not express reelin. These results raise the possibility that populations of pioneer neurons of the PP, including Cajal-Retzius cells, gain neuronal physiological properties early in development via expression of the Na(v)1.3 (SCN3) Na channel isoform. (+info)
Newborn horizontal cells migrate bi-directionally across the neuroepithelium during retinal development.
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Cell migration plays an important role during the development of the retina. In this work we have studied the migration of newborn horizontal cells in avian embryonic retina. Using the pattern of the early expressed transcription factors Lim1 and Prox1 we have shown that horizontal cells migrate bi-directionally from their site of birth, close to the ventricular side, to the adjacent (vitreal) side of the neuroepithelium, where they align just next to the prospective ganglion cell layer before migrating back again to their final laminar position in the external part of the inner nuclear layer. The migration occurs between Hamburger and Hamilton stages 24 and 33, which is equivalent to embryonic day 4.5 and 8. Between stages 26 and 30 the horizontal cells reside close to the ganglion cell layer and intra ocular injections of a cytochalasin D, an actin polymerisation blocker that inhibit migration, at stage 29 interfered with the migration of the horizontal cells to their final destination. Furthermore, using biolistic gene transfer with a green fluorescence protein expression vector of retinal slices we were able to record ventricle-directed migration by time-lapse microscopy. Combining biolistics with immunohistochemistry we showed that transfected cells, which have also been translocated in a ventricular direction were positive for the horizontal cell markers Lim1 and Prox1. The alternative path of migration that is described in this work differs from the generally accepted one for horizontal cells and this knowledge will influence the view of how the molecular determination of horizontal cells is specified. (+info)
NeuroD induces the expression of visinin and calretinin by proliferating cells derived from toxin-damaged chicken retina.
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Muller glia have been shown to be a potential source of neural regeneration in the avian retina. In response to acute damage Muller glia de-differentiate, proliferate, express transcription factors found in embryonic retinal progenitors, and some of the progeny differentiate into neurons and glia (Fischer and Reh [2001a] Nat. Neurosci. 4:247-252). However, most of the cells produced by proliferating Muller cells appear to remain undifferentiated. The purpose of this study was to test whether the neurogenic gene NeuroD can promote the differentiation of proliferating cells derived from the postnatal chick retina. We used recombinant avian retroviruses to transfect green fluorescent protein (GFP) or NeuroD. The majority of cells transfected with GFP remained undifferentiated, with a few cells differentiating into calretinin-immunoreactive neurons. Many cells transfected with the NeuroD-virus expressed calretinin, neurofilament, or visinin, while most cells remained undifferentiated. The number of calretinin-expressing cells that were generated was increased approximately 20-fold with forced expression of NeuroD. In addition, we found that cells transfected with NeuroD never expressed glutamine synthetase, a marker of mature Muller glia, suggesting that NeuroD suppresses glial differentiation. We conclude that NeuroD stimulates cells from the toxin-damaged chicken retina to acquire some neuronal phenotypes. We propose that most of these cells were derived from Muller glia. (+info)
Origins of cortical interneuron subtypes.
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Cerebral cortical functions are conducted by two general classes of neurons: glutamatergic projection neurons and GABAergic interneurons. Distinct interneuron subtypes serve distinct roles in modulating cortical activity and can be differentially affected in cortical diseases, but little is known about the mechanisms for generating their diversity. Recent evidence suggests that many cortical interneurons originate within the subcortical telencephalon and then migrate tangentially into the overlying cortex. To test the hypothesis that distinct interneuron subtypes are derived from distinct telencephalic subdivisions, we have used an in vitro assay to assess the developmental potential of subregions of the telencephalic proliferative zone (PZ) to give rise to neurochemically defined interneuron subgroups. PZ cells from GFP+ donor mouse embryos were transplanted onto neonatal cortical feeder cells and assessed for their ability to generate specific interneuron subtypes. Our results suggest that the parvalbumin- and the somatostatin-expressing interneuron subgroups originate primarily within the medial ganglionic eminence (MGE) of the subcortical telencephalon, whereas the calretinin-expressing interneurons appear to derive mainly from the caudal ganglionic eminence (CGE). These results are supported by findings from primary cultures of cortex from Nkx2.1 mutants, in which normal MGE fails to form but in which the CGE is less affected. In these cultures, parvalbumin- and somatostatin-expressing cells are absent, although calretinin-expressing interneurons are present. Interestingly, calretinin-expressing bipolar interneurons were nearly absent from cortical cultures of Dlx1/2 mutants. By establishing spatial differences in the origins of interneuron subtypes, these studies lay the groundwork for elucidating the molecular bases for their distinct differentiation pathways. (+info)