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Biomedical subjects

O T Jones

Publications and source records attributed to O T Jones.

At least 19 recordsLinked to original sources
PubMed2000

Internalization of the Kv1.4 potassium channel is suppressed by clustering interactions with PSD-95.

The contribution of voltage-dependent ion channels to nerve function depends upon their cell-surface distributions. Nevertheless, the mechanisms underlying channel localization are poorly understood. Two phenomena appear particularly important: the clustering of channels by membrane-associated guanylate kinases (MAGUKs), such as PSD-95, and the regional stabilization of cell-surface proteins by differential suppression of endocytosis. Could these phenomena be related? To test this possibility we examined the effect of PSD-95 on the internalization rate of Kv1.4 K(+) channels in transfected HEK293 cells using cell-surface biotinylation assays. When expressed alone Kv1.4 was internalized with a half-life of 87 min, but, in the presence of PSD-95, Kv1.4 internalization was completely suppressed. Immunochemistry and electrophysiology showed PSD-95 had little effect on total or cell-surface levels of Kv1.4 or on current amplitude, activation, or inactivation kinetics. Clustering was necessary and sufficient to suppress Kv1.4 internalization since C35S-PSD-95, a mutant reported to bind but not cluster Kv1.4, (confirmed by imaging cells co-expressing a functional, GFP-variant-tagged Kv1.4) restored and, surprisingly, enhanced the rate of Kv1.4 internalization (t((1)/(2)) = 16 min). These data argue PSD-95-mediated clustering suppresses Kv1.4 internalization and suggest a fundamentally new role for PSD-95, and perhaps other MAGUKs, orchestrating the stabilization of channels at the cell-surface.

Amino Acid Sequence↗
PubMed2000

Field evaluation of a slow release pheromone formulation to control the American bollworm, Helicoverpa armigera (Lepidoptera: Noctuidae) in Pakistan.

Trials to control the American bollworm, Helicoverpa armigera (Hübner) by the technique of mating disruption were carried out in the Pakistan Province of Punjab during the 1996 cotton season. A slow release PVC resin formulation, Selibate(R) HA, containing a 97:3 mixture of the major (9Z-hexadecenal) and minor (11Z-hexadecenal) components of the female sex pheromone of H. armigera was applied at a rate of 40 g active ingredient ha-1 during August 1996. The formulation was applied around the terminal portion of the cotton plant by hand using local labour at a rate of c. 250 pieces per hectare. The efficacy of the formulation was compared to conventional insecticide regimes to control H. armigera on four farmer practice fields situated at least 1 km to the north, south, east and west of the pheromone treated area. A high degree of trap catch shutdown (indicating mating suppression) was observed throughout the pheromone treated area during the whole of the season compared to non-pheromone treated farmer practice fields. Night observations confirmed that mating disruption occurred in the pheromone treated area as a smaller percentage of mated females were collected from this area compared to farmer practice fields. A majority of mated females collected from the pheromone treated area mated only once, whereas females in farmer practice fields had undergone multiple matings. A greater percentage of tethered female H. armigera moths retrieved from farmer practice fields had successfully mated compared to tethered females retrieved from the pheromone treated area. Release rate data of H. armigera pheromone from the formulation show that c. 70% was released during the two month trial period. However, the highly dispersive pre-oviposition flight behaviour of females meant that the area treated was not sufficient to eliminate the problem of gravid females migrating in from surrounding areas, and ovipositing therein. The implications of using the technique of mating disruption to control large strong flying insects like H. armigera are discussed.

Aldehydes↗
PubMed2000

Suppression of the rat microglia Kv1.3 current by src-family tyrosine kinases and oxygen/glucose deprivation.

Microglia activate following numerous acute insults to the brain, including oxygen/glucose deprivation (OGD), and both protein tyrosine kinases (PTKs) and K+ channels have been implicated in their activation. We identified Kv1.3 (voltage-gated potassium channel) protein in cultured rat microglia and confirmed that the native current is biophysically and pharmacologically similar to Kv1. 3. To explore whether src-family PTKs regulate the microglial Kv current, we first heterologously expressed Kv1.3 in a microglia-like cell line derived from neonatal rat brain (MLS-9). The resulting large Kv1.3 current was eliminated by co-transfecting the constitutively active PTK, v-src, then rapidly restored by the PTK inhibitor, lavendustin A. Acute activation of endogenous src kinases by a peptide activator significantly reduced the current, an effect that was mimicked by OGD. Similarly, in primary cultures of rat microglia, the endogenous Kv1.3-like current was inhibited by activating endogenous src-family PTKs and by OGD. Biochemical analysis showed that OGD increased the tyrosine phosphorylation of native Kv1.3 protein, which was alleviated by PTK inhibitors or reactive oxygen species (ROS) scavengers. Conversely, the basal level of Kv1.3 phosphorylation was decreased by PTK inhibitors or scavengers of ROS. Together, our results point to a post-insertional downregulation of the microglial Kv1.3-like current by oxidative stress and tyrosine phosphorylation. This interaction may be facilitated by a multiprotein complex because, in cultured microglia, the endogenous Kv1.3 and src proteins both bind to the scaffolding protein, post-synaptic density protein 95 (PSD-95). By associating with, and phosphorylating Kv1.3, src is well positioned to regulate microglial responses to oxidative stress.

Animals↗
PubMed2000

Abnormal axonal physiology is associated with altered expression and distribution of Kv1.1 and Kv1.2 K+ channels after chronic spinal cord injury.

Dysfunction of surviving axons which traverse the site of spinal cord injury (SCI) has been linked to altered sensitivity to the K+ channel blocker 4-aminopyridine (4-AP) and appears to contribute to post-traumatic neurological deficits although the underlying mechanisms remain unclear. In this study, sucrose gap electrophysiology in isolated dorsal column strips, Western blotting and confocal immunofluorescence microscopy were used to identify the K+ channels associated with axonal dysfunction after chronic (6-8 weeks postinjury) clip compresssion SCI of the thoracic cord at T7 in rats. The K+ channel blockers 4-AP (200 microM, 1 mM and 10 mM) and alpha-dendrotoxin (alpha-DTX, 500 nM) resulted in a significant relative increase in the amplitude and area of compound action potentials (CAP) recorded from chronically injured dorsal column axons in comparison with control noninjured preparations. In contrast, TEA (10 mM) and CsCl (2 mM) had similar effects on injured and control spinal cord axons. Western blotting and quantitative immunofluorescence microscopy showed increased expression of Kv1.1 and Kv1.2 K+ channel proteins on spinal cord axons following injury. In addition, Kv1.1 and Kv1.2 showed a dispersed staining pattern along injured axons in contrast to a paired juxtaparanodal localization in uninjured spinal cord axons. Furthermore, labelled alpha-DTX colocalized with Kv1.1 and Kv1.2 along axons. These findings suggest a novel mechanism of axonal dysfunction after SCI whereby an increased 4-AP- and alpha-DTX-sensitive K+ conductance, mediated in part by increased Kv1.1 and Kv1.2 K+ channel expression, contributes to abnormal axonal physiology in surviving axons.

4-Aminopyridine↗
PubMed2000

Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate.

PURPOSE: In this study, we assessed the effects of topiramate (TPM) on high-voltage-activated calcium channel (HVACC) currents in vitro. METHODS: HVACC currents were recorded from rat dentate gyrus granule cells by using whole-cell patch-clamp techniques. The biophysical properties of HVACCs were used to separate voltage-activated Ca2+ currents into different subtypes. Three concentrations of TPM were tested: 1, 10, and 50 microM. RESULTS: TPM inhibited L-type currents and was more effective at 10 microM than at 50 microM, suggesting that there may be an optimal concentration at which TPM decreases L-type currents. Non-L-type currents were transiently increased by TPM at a high concentration (50 microM). CONCLUSIONS: Because the location of L-type calcium channels on soma and proximal dendrites gives these channels a crucial role in controlling dendritic excitability and in providing calcium for intracellular effectors, the decrease in the L-type HVA Ca2+ currents may be an important anticonvulsant mechanism of TPM.

Action Potentials↗
PubMed1999

Kindling induces an asymmetric enhancement of N-type Ca2+ channel density in the dendritic fields of the rat hippocampus.

The mechanisms underlying epilepsy are largely unknown. Recent genetic, pharmacological and electrophysiological data indicate a significant, but poorly understood, role for voltage-dependent calcium channels (VDCCs). Since the contribution of ion channels to nerve function depends on their cell surface distribution, we hypothesized that epilepsy might alter VDCC surface densities. To test this idea we mapped the expression and distribution of fluorescent-labeled hippocampal N-type VDCCs (N-VDCCs) in an animal model of epilepsy, amygdala kindling. Image analysis demonstrated that kindling induced a 21-40% increase in N-VDCC expression in CA1 but not CA3. This increase occurred in the stratum radiatum and was twice as high in tissues contra- versus ipsi-lateral to the stimulating electrode. These data rationalize recent electrophysiology and argue that a persistent alteration in N-VDCC trafficking in dendrites or nerve termini may contribute to seizure-induced synaptic plasticity.

Animals↗
PubMed1999

Kindling induces a long-term enhancement in the density of N-type calcium channels in the rat hippocampus.

How seizures arise and recur in epilepsy is unknown. Recent genetic, pharmacological and electrophysiological data indicate a significant but undisclosed role for voltage-dependent calcium channels. Since the contribution such channels make to nerve function reflects the targeting of discrete subtypes to distinct cellular regions, we hypothesized that epilepsy reflects alterations in their spatiotemporal patterns of expression at the cell surface. To test this possibility, we examined the expression and distribution of hippocampal N-type calcium channels in an animal seizure model: kindling. Confocal microscopy of N-type calcium channels labeled with a new fluorescent ligand, coupled with a novel technique for analysing multiple images, revealed a 20-40% increase in their expression in CA1 and CA3 within 24 h post-seizure. These increases persisted in the dendritic fields of CA1, but had dissipated in CA3 by 28 days post-seizure. Such changes correlate poorly with cell number or synaptogenesis, but are consistent with increased N-type calcium channel expression on presynaptic terminals or, more likely, dendrites. These data rationalize recent electrophysiology and in situ hybridization data, and suggest that kindling alters N-type calcium channel trafficking mechanisms to cause a persistent, local, remodeling of their distributions in CA1 dendrites. The persistent induction of N-type calcium channels may be part of a mechanism for, and a hallmark of, synaptic plasticity, in which kindling represents a reinforcement of synapses en masse.

Animals↗
PubMed1998

Keratinocyte superoxide generation.

We have demonstrated using the reduction of cytochrome c, that the keratinocyte cell line H357 generates superoxide at significant rates (8.36 nmol/h/10[6] cells). The rate of superoxide release decreased as the cells reached confluence. Superoxide production was increased more than twofold following preincubation with IL-1beta, or by the addition of the Ca2+ ionophore, Ionomycin. Other stimuli known to activate the NADPH oxidase of phagocytes were ineffective, but the regulatory cytokine IFNgamma lowered the rate of release. Inhibitors of lipoxygenase function decreased the rate of superoxide production, whereas inhibitors of cyclo-oxygenase, xanthine oxidase, or NADPH oxidase failed to inhibit. The addition of NADH or NADPH to whole cells increased the rate threefold.

Cytochrome c Group↗
PubMed1998

Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation.

The A-to-G mutation at position 8344 in the transfer RNAlysine mitochondrial DNA gene is associated mostly with the myoclonic epilepsy and ragged red fibers syndrome. We describe a five-generation family with this mutation and 19 affected members with a variant neurologic syndrome of ataxia, myopathy, hearing loss, and neuropathy. Along with axial lipomas and diabetes mellitus, hypertension is a frequent somatic feature, suggesting that mitochondrial mutations may contribute to hypertension in these patients.

DNA, Mitochondrial↗
PubMed1997

Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle.

1. In rat heart, three K+ channel genes that encode inactivating transient outward (ITO)-like currents are expressed. During development the predominant K+ channel mRNA species switches from Kv1.4 to Kv4.2 and Kv4.3. However, no functional correlate of this isoform switch has been reported. We investigated action potential characteristics and ITO in cultured neonatal rat ventricular myocytes and adult rat hearts. We further examined whether the changes in K+ channel gene expression and the associated electrophysiology that occurs during development could be induced by thyroid hormone. 2. In myocytes isolated from right ventricle of adult rat heart, action potential duration was short and independent of rate of stimulation. The density of ITO was 21.5 +/- 1.8 pA pF-1 (n = 21). Recovery from inactivation was best described by a single exponential (tau fast = 31.7 +/- 2.7 ms, n = 13). The current remaining at the end of a 500 ms pulse (ISUS) was 6.2 +/- 0.5 pA pF-1 (n = 19). 3. In contrast to adult cells, action potential duration was prolonged and was markedly rate dependent in cultured neonatal rat ventricular myocytes. The current density of ITO measured in cultured ventricular myocytes from 1- to 2-day-old rats was 10.1 +/- 1.5 pA pF-1 (n = 17). The recovery from inactivation for ITO was best described by the sum of two exponentials (tau fast = 64.3 +/- 8.8 ms, 54.4 +/- 10.2%; tau slow = 8216 +/- 2396 ms, 37.4 +/- 7.9%; n = 5). ISUS was 4.4 +/- 0.6 pA pF-1 (n = 17). Steady-state activation and inactivation were similar in adult and neonatal ventricular myocytes. 4. In neonatal myocytes treated with thyroid hormone, tri-iodothyronine (T3, 100 nM), action potential duration was abbreviated and independent of stimulation rate. Whilst T3 did not significantly increase ITO density (24.0 +/- 2.9 pA pF-1; n = 21 in T3 treated cells cf. 20.1 +/- 3.0 pA pF-1; n = 37 in untreated controls), the recovery from inactivation of ITO was accelerated (tau fast = 39.2 +/- 3.6 ms, 82.2 +/- 8.9%, n = 9). T3 did however, increase ISUS current density (4.7 +/- 0.77 pA pF-1; n = 37 and 7.0 +/- 0.7 pA pF-1, n = 21, in control and T3 treated cells, respectively. 5. The effects of T3 (100 nM) were associated with a marked decrease in the expression of Kv1.4 at the mRNA and protein level, and an increase in the expression of Kv4.3 without changes in Kv4.2 mRNA levels. 6. The findings of the present study indicate that postnatal development involves a shortening of action potential duration and an increase in the density of ITO. Furthermore, we show that development is also associated with a loss of action potential rate dependence, and an acceleration in the rate of recovery of ITO. We propose that these functional effects occur as a consequence of the previously reported developmental Kv1.4 to Kv4.2/Kv4.3 isoform switch. In cultured neonatal myocytes, T3 induced many of the electrophysiological and molecular changes that normally occur during postnatal development, suggesting that this hormone may play an important role in postnatal electrophysiological development.

Action Potentials↗
PubMed1997

Impact of cytoplasmic calcium buffering on the spatial and temporal characteristics of intercellular calcium signals in astrocytes.

The impact of calcium buffering on the initiation and propagation of mechanically elicited intercellular Ca2+ waves was studied using astrocytes loaded with different exogenous, cell membrane-permeant Ca2+ chelators and a laser scanning confocal or video fluorescence microscope. Using an ELISA with a novel antibody to BAPTA, we showed that different cell-permeant chelators, when applied at the same concentrations, accumulate to the same degree inside the cells. Loading cultures with BAPTA, a high Ca2+ affinity chelator, almost completely blocked calcium wave occurrence. Chelators having lower Ca2+ affinities had lesser affects, as shown in their attenuation of both the radius of spread and propagation velocity of the Ca2+ wave. The chelators blocked the process of wave propagation, not initiation, because large [Ca2+]i increases elicited in the mechanically stimulated cell were insufficient to trigger the wave in the presence of high Ca2+ affinity buffers. Wave attenuation was a function of cytoplasmic Ca2+ buffering capacity; i.e., loading increasing concentrations of low Ca2+ affinity buffers mimicked the effects of lesser quantities of high-affinity chelators. In chelator-treated astrocytes, changes in calcium wave properties were independent of the Ca2+-binding rate constants of the chelators, of chelation of other ions such as Zn2+, and of effects on gap junction function. Slowing of the wave could be completely accounted for by the slowing of Ca2+ ion diffusion within the cytoplasm of individual astrocytes. The data obtained suggest that alterations in Ca2+ buffering may provide a potent mechanism by which the localized spread of astrocytic Ca2+ signals is controlled.

Animals↗
PubMed1997

Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene.

Potassium channels play a key role in the regulation of membrane excitability. We investigated the gene expression response of the Kv4.2 subtype of potassium channel, in the rat hippocampus, to a brief (5 min) episode of kainic acid-induced seizures. Our results demonstrate that Kv4.2 expression is reduced in the granule cell layer of the dentate gyrus at 3 h post-seizure, while no significant changes in expression are observed in other hippocampal subfields. At 6 h post-challenge, expression in both dentate hilar cells and granule cells is reduced, while no other significant changes are observed. At 24 h post-challenge, expression levels for Kv4.2 in the dentate granule cells have rebounded to levels greater than control, while expression levels are significantly reduced in the CA3 and CA4 subfields. No significant changes in Kv4.2 expression are observed in kainic acid-administered animals that fail to seize, indicating that the changes in gene expression result from seizure activity and not from the direct actions of the administered kainic acid. These results demonstrate that brief kainic acid-induced epileptiform activity promotes alterations in the expression levels for the Kv4.2 subtype of potassium channel gene.

Animals↗
PubMed1997

N-Type calcium channels in the developing rat hippocampus: subunit, complex, and regional expression.

The expression of multiple classes of voltage-dependent calcium channels (VDCCs) allows neurons to tailor calcium signaling to functionally discrete cellular regions. In the developing hippocampus a central issue is whether the expression of VDCC subtypes plays a role in key phases such as migration and synaptogenesis. Using radioligand binding and immunoblotting, we show that some N-type VDCCs exist before birth, consistent with a role in migration; however, most N-VDCC subunit expression is postnatal, coinciding with synaptogenesis. Immunoprecipitation studies indicate that the increased expression of N-VDCCs in early development occurs without subunit switching because there is no change in the fraction of beta3 subunits in the N-VDCC alpha1B-beta3 heteromers. Fluorescence imaging of cell surface N-VDCCs during this period reveals that N-VDCCs are expressed on somata before dendrites and that this expression is asynchronous between different subfields of the hippocampus (CA3-CA4 before CA1-CA2 and dentate gyrus). Our data argue that N-VDCC expression is an important cue in the genesis of synaptic transmission in discrete hippocampal subfields.

Animals↗
PubMed1997

A novel use for a carbodiimide compound for the fixation of fluorescent and non-fluorescent calcium indicators in situ following physiological experiments.

The inability to determine the precise intracellular location of non-fluorescent organic calcium chelators such as BAPTA is a persistent problem which has precluded much detailed analysis of the chelators' spatial or temporal dynamics in live cells. Similarly, following physiological experiments with fluorescent indicators like Fura-2, it has often been desirable to maintain the dye within the cell for later analysis by additional histological techniques. Based on chemical considerations, and its prior use in tissue fixation, we examined the water soluble reagent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) as a potential fixative for diverse calcium chelators. The utility of EDC, but not other common fixatives, was confirmed through electrophysiological means, through a novel ELISA, which exploits anti-BAPTA antibodies to assess the extent and kinetics of fixation; by autoradiography of neurons loaded with [14C]-BAPTA, and by immunocytochemistry and imaging of intracellular BAPTA or Calcium Green in neurons. At concentrations > 0.1 mg/ml, EDC caused virtually instantaneous, irreversible, fixation of > 95% of BAPTA free acid. Fixation of intracellular BAPTA was confirmed in hippocampal brain slices loaded with BAPTA/AM ester, and showed biphasic kinetics consistent with rapid loading and subsequent extrusion of the chelator. Immunocytochemistry on neurons microinjected with BAPTA free acid and the dye Lucifer Yellow showed BAPTA-specific staining which was distributed in the cell similarly to that of the accompanying marker dye. Application of EDC also efficiently fixed in situ analogs of BAPTA such as Calcium Green (a fluorescent Ca2+ indicator) as shown by confocal imaging of EDC-fixed brain slices loaded with this indicator. Taken together, these data show that EDC is an effective, inexpensive and versatile fixative for calcium chelators in diverse cells. The availability of a suitable fixative now makes it possible to determine the distributions of such chelators at both the light and, possibly, the electron microscope level. Two important features of EDC, arise from its specificity for free carboxyl groups. First, the ability to fix, selectively, the chelators but not their AM esters; and, second, its enormous potential as a fixative for the numerous other carboxyl-containing chelators, dyes and pH indicators currently available.

Animals↗
PubMed1997

Preparation, characterization and utility of a novel antibody for resolving the spatial and temporal dynamics of the calcium chelator BAPTA.

In spite of its importance as a tool to manipulate cell calcium, the versatility of the octadentate chelator BAPTA in cell physiological and diverse other applications is limited by the difficulty with which it can be quantified and its cell and tissue distributions determined. Conventional approaches, such as HPLC analysis or autoradiography, are of limited sensitivity and resolution and have attendant biohazard risks. We now describe a versatile, facile and inexpensive means for quantifying and determining the distribution of BAPTA which exploits an immunological approach based on our generation of novel antibodies to BAPTA. Antibodies to BAPTA were prepared by immunizing rabbits with BAPTA conjugated to keyhole limpet hemocyanin via a zero-order cross-linking reagent-EDC. The ability of anti-BAPTA IgGs to recognize free or conjugated BAPTA was confirmed using enzyme-linked and immunoblotting assays made possible by our introduction of a BAPTA-BSA adduct. Using such assays, we show that the anti-BAPTA antibodies possess marked selectivity for BAPTA compared to several structurally-related BAPTA analogs. The utility of the anti-BAPTA antibodies in cell calcium research has been confirmed in two ways. First, by determining the spatial distribution of BAPTA through immunocytochemistry and confocal microscopy of cortical neurons loaded with BAPTA/AM and, second, by determination of the kinetics of loading and efflux of BAPTA through enzyme-linked cell immunoassays (ELISA) and immunocytochemistry. Together, these data demonstrate that anti-BAPTA antibodies are a powerful new tool with which to quantify BAPTA and to define the spatial and temporal distribution of this important calcium chelator in live cells. Such information should greatly aid the design of cell physiological experiments, the development of new chelators and the identification of sources of chelator selectivity in emerging therapeutic applications.

Animals↗
PubMed1997

Effect of simvastatin therapy on cell membrane cholesterol content and membrane function as assessed by polymorphonuclear cell NADPH oxidase activity.

Cell membrane cholesterol is an important determinant of membrane fluidity. Changes in fluidity have important consequences for membrane function. Treatment of hypercholesterolaemia could therefore affect membrane function by reducing cell membrane cholesterol levels. The aim of this study was to determine whether treatment with simvastatin affects membrane cholesterol and the activity of the polymorphonuclear cell membrane enzyme NADPH oxidase. Blood was obtained from 12 hypercholesterolaemic patients before, and 6 weeks after, treatment with simvastatin, and from 20 normolipidaemic subjects. Cell cholesterol was in the unesterified from indicating that it was membrane-associated. Pre-treatment mean cell cholesterol concentration in the hyperlipidaemics was higher (P < 0.05) than in the normolipidaemics [4.19 fmol/cell, 95% confidence interval (CI) 3.38-5.05 versus 3.10 fmol/cell, 95% CI 2.58-3.61]. There was a strong correlation between cell cholesterol content and NADPH oxidase lag phase (R(s) = 0.76, P < 0.01). Cell cholesterol fell to 3.52 fmol/cell (95% CI 2.77-4.28, P < 0.05) following treatment and there was a correlation (R(s) = 0.61, P < 0.05) between the reductions in cell cholesterol and lag phase.

Adult↗
PubMed1996

Three distinct neuronal phenotypes exist in embryonic rat hippocampal neurons cultured in basic fibroblast growth factor.

The possibility that neurons cultured in basic fibroblast growth factor (bFGF) are heterogeneous raises concerns about their subsequent use in gene transfection and transplantation studies. We have examined the fate of embryonic hippocampal neurons in bFGF culture, and now conclude that these cells are not only heterogeneous, but possess neurons of various stages of development. Morphological and immunocytochemical analysis reveal three distinct developmental classes of neurons are present in extended bFGF culture. This tripartite classification is supported by electrophysiological analysis, which reveals that upon depolarization, neurons with precursor and juvenile neuron morphologies are unable to fire action potentials. The third class of neurons, which resemble age-matched polarized neurons in standard serum culture, fired multiple action potentials indicative of a mature phenotype. These data show neurons at multiple developmental stages co-exist in bFGF culture, and provide an experimental basis for their classification.

Action Potentials↗