, 1989, Galli and Maffei, 1988, Garaschuk et al , 1998, O’Donovan

, 1989, Galli and Maffei, 1988, Garaschuk et al., 1998, O’Donovan et al., 1994, Wong et al., 1995 and Yuste et al., 1992). Frequently, this form of activity travels across brain regions as waves activating neighboring neurons simultaneously. This particular property of intrinsically generated activity in developing networks is thought to be an important component of the activity-dependent establishment of specific brain circuits. For example, the high degree of correlation between neighboring neurons helps maintaining their spatial relationship through ascending neuronal pathways and thus establishing a topographic organization at

all levels (e.g., Triplett et al., 2009). Although the patterns MK-2206 ic50 of spontaneous activity at the level of

networks and individual neurons have been described in great detail, the activity patterns at the level of individual synapses within the dendritic arborization of single neurons are not known. It has been clear for some time that—within one neuron—spontaneous network events are frequently manifested as barrages or bursts of coincident synaptic inputs (Ben-Ari et al., 1989). However, how these synaptic inputs are distributed click here across the dendritic tree has not been investigated, mostly due to the fact that electrophysiological measurements do not allow identifying the dendritic locations of synaptic inputs. In mature neurons, the location of synaptic inputs within the dendritic arborization is most likely Calpain crucial for processing and storing information. For example, in tadpoles the dendrites of individual tectal neurons receive topographically organized afferent inputs (Bollmann and Engert, 2009). In mice, pyramidal neurons of the visual and auditory cortex receive functionally diverse synaptic inputs that are integrated by the postsynaptic cell to generate highly specific output (Chen et al., 2011 and Jia et al., 2010). Dendritic integration in pyramidal neurons has been shown to be supra-linear and—as

a consequence—the simultaneous activation of several synapses that are located close to each other on the same dendrite have a stronger influence on neuronal firing than the activation of the same number of synapses on different branches (Branco and Häusser, 2010, Larkum and Nevian, 2008, Losonczy and Magee, 2006 and Polsky et al., 2004). Furthermore, theoretical work demonstrated that such a local integration scheme where information is computed in dedicated dendritic subunits can boost the information processing capacities of neurons dramatically (Häusser and Mel, 2003, Poirazi and Mel, 2001 and Spruston, 2008). Here, we asked whether the patterns of synaptic input that developing hippocampal pyramidal neurons receive during spontaneous network bursts may already reflect such a subcellular fine-scale organization.

These data suggest a presence of a potential compensatory mechani

These data suggest a presence of a potential compensatory mechanism that maintains the total level of sAPP in the brain regardless of ADAM10 expression levels. We also measured the levels of secreted APP (sAPPα, sAPPβ,

and total sAPP) in cerebrospinal fluid (CSF) and found similar patterns depending on the ADAM10 genotypes (Figure S2A). Levels of endogenous Aβ40 and Aβ42 (measured by ELISA) were significantly lower in ADAM10-WT mice compared to the nontransgenic controls, while the levels were dramatically higher in ADAM10-DN mice (Figure S2B). For mice expressing either Q170H or R181G mutations, a trend was observed in which endogenous Aβ levels were increased compared to ADAM10-WT mice. Taken together, these data reveal that both ADAM10 LOAD prodomain

mutations attenuate but do not entirely abolish α-secretase activity of ADAM10 on www.selleckchem.com/products/Y-27632.html APP. Next, we asked selleck screening library whether the prodomain mutations affect the cleavage of other ADAM10 substrates besides APP (Pruessmeyer and Ludwig, 2009). We examined the processing of candidate ADAM10 substrates in the brain including APLP2, Notch1, and N-cadherin. The processing of APLP2 showed very similar patterns to those of APP in that ADAM10-WT overexpression resulted in the increased cleavage of mature APLP2, while this was attenuated in mice expressing either of the two LOAD mutations (Figure S2C). Interestingly, ∼57-kDa-sized C terminus-truncated soluble APLP2, analogous to

the soluble APP cleavage product, was detected more abundantly in ADAM10-WT than the LOAD mutant mouse brains. In contrast, western blot analysis of adult brains and primary neurons derived from ADAM10 transgenic mice showed ADAM10 overexpression barely affected N-cadherin level or N-cadherin-CTF generation (Figure S2D). In contrast to embryonic brains, most nearly of Notch1 protein in adult brains is cleaved and present as extracellular truncated forms in the membrane. We found that neither WT nor mutant ADAM10 overexpression changed the level of full-length or truncated forms of Notch1 (Figure S2E). Together, these data suggest that the processing of APP family proteins is particularly vulnerable to loss-of-function mutations in ADAM10. To evaluate the effects of the two LOAD ADAM10 mutations on AD pathogenesis, we crossed transgenic mice expressing WT or mutant forms of ADAM10 with Tg2576 AD mice and assessed APP processing, Aβ levels, and amyloid plaque load. As in the ADAM10 transgenic mice, the prion protein promoter was utilized in the Tg2576 mice to express human APPswe. Western blot analysis of mouse brain lysates revealed that APP expression was several-fold higher in Tg2576 mice than in nontransgenic control. However, ADAM10 expression in Tg2576/ADAM10 double-transgenic mice was maintained at similar levels to those in parental ADAM10 single-transgenic mice (Figures 2A and S3A).

The complexity of this is further compounded,

as directly

The complexity of this is further compounded,

as directly investigating hetereosynaptic synergism and/or competition should optimally be performed in the intact brain where all of the functional connectivity is preserved. To tackle this, Calhoon and O’Donnell (2013) NVP-BKM120 in vivo performed sharp electrode recordings from VS MSNs in anesthetized rats while examining how electrical stimulation of the prefrontal cortex (PFC) altered MSN responses to electrical stimulation of either hippocampal input via the fimbria-fornix or thalamic input. Strong burst-like stimulation of the PFC, comparable to the firing patterns observed in some PFC neurons during behavioral tasks (Peters et al., 2005), produced subthreshold learn more depolarization in VS MSNs but rarely led to robust spiking. Surprisingly, when either fornix or thalamic stimulation was delivered immediately after PFC stimulation, instead of an expected summation of excitatory responses that produced even

more robust MSN activation, the responses induced by thalamic and hippocampal inputs were attenuated, suggesting that heterosynaptic competition may exist between VS excitatory synaptic inputs, analogous to phenomena seen in other brain regions (Fuentealba et al., 2004). Importantly, direct depolarization comparable in amplitude and duration to those induced by PFC stimulation did not Calpain attenuate hippocampal or thalamic MSN responses, suggesting that it is not depolarization

per se that can account for PFC-induced suppression of competing inputs. While a number of potential candidate cellular and circuit mechanisms exist that could account for an attenuation of hippocampal and thalamic input by PFC activation, one interesting possibility is that PFC innervation also activates inhibitory neurons within the VS, such as fast-spiking interneurons (FSIs). FSIs make up <1% of the neuronal composition of the VS (Luk and Sadikot, 2001) but have potent inhibitory network effects. In addition, VS FSIs show entrainment with cortical oscillations (Berke, 2009; Gruber et al., 2009a), suggesting direct or indirect functional connectivity between VS FSIs and PFC activity. To examine whether inhibitory processes, such as the activity of VS FSIs may regulate heterosynaptic suppression of hippocampal inputs by PFC stimulation, Calhoon and O’Donnell (2013) introduced open channel GABAA blockers intracellularly via sharp electrodes in some experiments. Blockade of GABAA receptors in VS MSNs produced greater excitation, including the induction of action potentials in response to PFC stimulation as well as reduced heterosynaptic suppression, suggesting that these processes were at least partially mediated by GABAA signaling onto MSNs. The activity of VS MSNs are often entrained to hippocampal activity (Berke et al.

With this motif, the feedback loop involves only the inhibitory u

With this motif, the feedback loop involves only the inhibitory units and the two synapses that connect them. In contrast, all other feedback architectures involve additional units and synapses in the feedback loop. We studied the consequences of structural complexity of the feedback motif on the ability

of the model to compute steady-state responses to competing stimuli rapidly and reliably. We compared the performance of the reciprocal inhibition of feedforward lateral inhibition motif (Figure 4, circuit 2) with that of the next most structurally simple motif: feedback lateral inhibition by output units (Figure 7A, circuit 3). The parameter values for the circuit 2 model were chosen to be the same as those in Figure 5E. The parameter values for the circuit 3 model were chosen such that the circuit yielded output unit responses AG-014699 supplier HDAC inhibitor at steady state that were nearly identical to those from the circuit 2 model (Figures S5A–S5D). The quality of the match between the responses of the two circuits was particularly sensitive to the values of the parameters for circuit 3, with the best match occurring over a narrow range of values (Figures S5E–S5J). We measured calculation speed as the settling time, defined as the first time step after which responses did not change any further (Experimental Procedures). The time courses of the responses from the two models, calculated

for an RF stimulus of strength Ketanserin of 9°/s and a competitor strength of 8°/s (relative strength = 1°/s), demonstrated that circuit 2 settled faster than circuit 3 (Figure 7E). This finding held true for all relative stimulus strength values (Figure 7F). Both models exhibited longer settling times as the relative strength between the competing stimuli decreased, consistent with the experimental observation that difficult discriminations take longer to resolve (Gold and Shadlen, 2007).

We assessed the reliability of the calculation as the consistency of the steady-state response. Gaussian noise was introduced into the calculation of the response for each unit at each time step. Consistency was quantified by calculating the Fano factor (Experimental Procedures), a metric that is inversely related to response consistency. The distribution of Fano factors at steady state was estimated using Monte Carlo analyses (Experimental Procedures). Comparison of the Fano factors from the two models for an RF stimulus of strength of 9°/s and a competitor strength of 8°/s (relative strength = 1°/s) showed that circuit 2 produced less variability (smaller Fano factor) than circuit 3 (Figure 7G; average Fano factors were 0.71 ± 0.01 and 0.78 ± 0.01, respectively; p < 10−4, rank-sum test). Circuit 2 exhibited superior reliability for all values of the RF stimulus from 1°/s to 9°/s (competitor = 8°/s), with the reduction in Fano factor being substantial (approximately 75%) when the RF stimulus was weaker or as strong as the competitor (Figure 7H).

, 2010) OHC forces generated from changes in length of the cell-

, 2010). OHC forces generated from changes in length of the cell-body are attributed to perturbations in cell membrane potential triggered by current entering through the mechanotransduction (MT) channels in the stereocilia.

These somatic forces have been traced to the protein prestin that is densely packed into the cell’s basolateral membrane, and which undergoes rapid changes of area when the receptor potential changes. Isolated OHCs generate forces in response to voltage stimuli I-BET-762 nmr up to at least 80 kHz (Frank et al., 1999). In the intact cochlea, however, the electrical filtering effect of the cell membrane, effectively possessing an electrical time constant = RmCm, would reduce potential changes to negligible levels at

any significant acoustic frequencies. Consequently, even though prestin-knockout mice are deaf (Liberman et al., 2002 and Mellado-Lagarde et al., 2008), the proposal that the prestin-dependent cell body forces account for functional amplification in the Vorinostat cochlea has never quite held together. The central issue is known as the “RC time-constant problem.” There have been numerous solutions proposed to address this conundrum. However, the paper by Johnson et al. (2011) in this issue of Neuron indicates a clear way out of the impasse for prestin-based mechanisms, for it shows that the OHC time constants may have been significantly overestimated. Methods for recording in the mammalian cochlea have developed slowly compared to recordings Resveratrol made in other vertebrate species, and it is only relatively recently that reliable recordings of transduction currents have been made

from mature mammalian hair cells. Johnson et al. (2011) have recorded from both rats and gerbils where OHCs can be selected from known frequency points along the cochlea. By measuring the transduction and basolateral membrane currents in OHCs from different cochlear positions in excised cochleas, the paper shows that the OHC membrane filtering may be an order of magnitude less than previously thought. As a result, receptor potentials would be uniformly larger. The authors present several lines of experimental evidence to support these arguments. First, they find that MT channel currents are significantly larger when recorded from OHCs taken toward the high-frequency end of the cochlea. This observation has been inferred several times from in silico cochlear model studies (Mammano and Nobili, 1993 and Ramamoorthy et al., 2007) and is seen in data from nonmammalian cochleas, but the records here show the effect clearly in mammalian hair cells. Second, the paper shows that resting transducer currents, irrespective of cochlear place of origin, are further enhanced when the OHC stereocilia face low Ca2+ concentrations (20 μM) as they do in the living cochlea (in vivo the stereocilia project into a low Ca2+/high K+ containing compartment, referred to as the scala media).

To determine to which extent the scattered Pax6+ cells maintain t

To determine to which extent the scattered Pax6+ cells maintain their RG identity and to examine their characteristic radial morphology, we next stained for nestin and RC2 to reveal the

radial glial processes (Figures 3I, 3J, 3M, and 3N). This also revealed scattered cell somata Abiraterone clinical trial and rather disorganized processes, which were no longer aligned and radially oriented in the cKO cerebral cortex (Figures 3N and 3N′) in contrast to controls (Figure 3M). The loss of apical anchoring of radial glial cells (see above as indicated by the scattered Pax6+ cells and below for F-actin analysis) further contributed to the disorganized arrangement of radial glia

cell somata and processes. Indeed, many cells located apically had lost their adherens junction anchoring (Figure S7) but were still able to form points of adhesion as also visible in rosette-like structures MLN8237 nmr sometimes observed between nestin+ cells in the cKO cerebral cortices with processes emanating radially and in rare cases directed to the pial or ventricular surface (Figure 3N′). As it appeared from these stainings that RG processes do no span the radial thickness of the cKO cerebral cortex, we examined this more globally by applying the lipophilic tracer DiO onto the surface of the cortices. As described previously (Malatesta et al., 2000), this label spreads along RG processes to their somata located in the ventricular zone (VZ; Figure 3K). In the cKO cortices, however, DiO-labeled processes were arranged in a very disorganized manner, and only few labeled processes reached the VZ (Figure 3L). Interestingly, the bulk of the DiO-labeled processes ended in the middle of the cerebral cortex, consistent with the idea that the upper and lower halves of the cKO else cerebral cortex are no longer connected by radial processes. The above data suggest that aberrations in radial glial cells, the main guides for migrating pyramidal neurons,

may be responsible for the failure of many neurons to reach their normal position. However, RhoA may also affect neuronal migration directly by affecting the cytoskeleton in migrating neurons as previously suggested (Besson et al., 2004, Heng et al., 2010 and Nguyen et al., 2006). To test these possibilities, we first electroporated CreGFP or GFPonly plasmids into the cerebral cortex of E14 RhoAfl/fl embryos to delete RhoA in few cells and examined RhoA levels 1 day later ( Figure S6). Consistent with the fast reduction of RhoA protein, we observed a notable reduction of RhoA-immuno-reactivity in the electroporated regions compared to neighboring parts, where no electroporated cells were located ( Figures S6A–S6C).

In these experiments, the amplitude of dendritic bAPs also remain

In these experiments, the amplitude of dendritic bAPs also remained unaltered during the train (Figure 1L). In addition, we never observed signs of dendritic regenerative potentials during bursts of action potentials, indicating a relatively low density of voltage-gated channels recruited by trains of bAPs. The strong attenuation of bAPs during invasion into granule cell dendrites raises the question if the associated Ca2+ transients Dolutegravir also show a distance-dependent attenuation. Using multiphoton Ca2+ imaging, we found that Ca2+ transients associated with single bAPs showed little attenuation in the first, larger caliber dendrite segments up to approximately 50 μm from the

soma (Figure 1M). Subsequently, however, attenuation was substantial toward more distal sites (Figures 1M and 1N, decrease for distances >50 μm from the soma 35.5% ± 0.4%/100 μm, 124 linescans,

n = 14 cells). Similar attenuation was observed for action potential bursts elicited by brief current injections (5 APs at 20 Hz, n = 3, 26 linescans, see Figure S1D available online). This is markedly different from pyramidal basal INCB024360 in vivo dendrites, in which no appreciable attenuation of bAP-associated Ca2+ transients is observed even when bAP amplitudes are markedly attenuated. The dendritic back-propagation of action potentials in pyramidal neurons is substantially modulated by voltage-gated Na+ channels (Colbert et al., 1997, Jung et al., 1997, Spruston et al., 1995, Stuart et al., 1997b and Stuart and Sakmann, 1994). Because the dendritic recordings so far suggested a comparatively low Parvulin density of Na+ currents in granule cell dendrites, we examined whether dendritic Na+ channels affect AP back-propagation in dentate granule cells by locally applying the Na+

channel blocker tetrodotoxin to granule cell dendrites during dual somatodendritic recordings (TTX, 1 μM, n = 4, average distance of application site from soma 167.9 ± 13.8 μm, Figures 2A–2D). During continuous local application of TTX, the somatic AP was initially unaffected, but bAP amplitudes decreased (red symbols in Figure 2B, see example traces at time point 2). Twenty seconds after onset of TTX application, the dendritic to somatic amplitude ratio was reduced by 12.6% ± 8.9% (n = 4). Ultimately, TTX application caused failure of somatic action potentials in all experiments (example traces at time point 3 in Figure 2B), indicating TTX had reached the perisomatic region including the axon initial segment. Just before the somatic action potential failed, the dendritic to somatic AP amplitude ratio was reduced by 42.7% ± 10.2% (summary in Figure 2C). Because the recruitment of voltage-gated Na+ currents is dependent on the membrane potential, which may be more depolarized in vivo, we also examined action potential back-propagation over a range of membrane potentials.

Manipulations of the SP/NK1R system have been shown to influence

Manipulations of the SP/NK1R system have been shown to influence several addiction-related GDC0199 behaviors. For example, NK1R knockout mice do not display morphine-CPP and self-administer morphine at lower rates. Morphine-induced locomotor activation

and psychomotor sensitization are also blunted in these mice (Murtra et al., 2000; Ripley et al., 2002). Lesions of NK1R-containing neurons in the AMG, but not NAC, suppressed morphine-induced CPP, a finding suggesting that NK1Rs in the AMG contribute to rewarding properties of morphine (Gadd et al., 2003). Reduced opioid reward after NK1R blockade was recently also supported by observations that this treatment attenuates the ability of morphine to lower intracranial self-stimulation thresholds (Robinson et al., 2012). Coadministration of SP and morphine prevents the internalization and acute desensitization of the mu opioid receptor typically induced by morphine, which may account for the involvement of the NK1R in opioid reward (Yu et al., 2009). These data collectively support a role of NK1R activation in rewarding properties of opioids and suggest the possibility that NK1R antagonists may be useful for the treatment of opioid addiction through blockade of opioid reward. Surprisingly,

however, an initial human laboratory study found that a single administration of the NK1R antagonist aprepitant potentiated, rather than inhibited, subjective as well as physiologic responses to an opioid challenge in prescription opioid abusers (Walsh et al., 2012). A direct assessment of opioid self-administration after NK1R blockade is therefore critical but has to date not been obtained in laboratory animals or humans. Furthermore, the Selleck LDN 193189 role of the NK1R in opioid-related behaviors influenced by stress, for example, stress-induced reinstatement of opioid seeking after extinction, has not been explored. In contrast to its role in opioid-related behaviors, disruption of NK1R signaling does not affect cocaine CPP, self-administration, or locomotor sensitization (Gadd et al., 2003; Murtra et al., 2000; Ripley et al., 2002). However, there is some evidence that NK1R antagonists tuclazepam can suppress

cocaine-induced locomotion (Kraft et al., 2001) and that relapse to cocaine seeking after extinction can be triggered by ICV infusion of a specific NK1R agonist (Placenza et al., 2005) or intra-VTA infusion of an SP analog (Placenza et al., 2004). However, an NK1R specific antagonist was unable to prevent reinstatement of cocaine seeking induced by cocaine priming (Placenza et al., 2005). One possibility is therefore that exogenous SP is able to activate pathways involved in reinstatement of cocaine seeking, but that this does not reflect actions of endogenous SP. Alternatively, cocaine-induced reinstatement may be mediated by an NK receptor other than NK1R, such as NK3R. Finally, it is possible that the NK1R is involved in reinstatement of cocaine seeking triggered by some stimuli, but not that induced by drug priming.

At the end of training, starlings were presented with random nond

At the end of training, starlings were presented with random nondifferentially reinforced (with secondary reinforcer only) probe stimuli consisting of each of the eight training motifs in isolation (i.e., not paired) to obtain behavioral confirmation that all four task-relevant motifs were recognized ( Figures 1E and 1F). Probe stimuli were randomly interleaved on 8%–20% of all trials during these probe sessions. Starlings were anesthetized with urethane (20% by volume, 7–8 ml/kg) and head fixed to a stereotactic apparatus inside a sound-attenuating chamber. A small craniotomy was made dorsal to CLM, and multichannel silicon electrode arrays (177 μm2 electrode surface area, 50 μm spacing, 1 × 16 and 1 × 32 electrode

layout; NeuroNexus technologies) were inserted into CLM. For some Rucaparib subjects, only the 1 × 32 array was used (Figure S2M). Motif stimuli were presented free field from a speaker 30 cm from the bird at sound pressure levels matched to those during behavioral training (mean, 65 dB; peak, 96 dB). Electrode arrays were advanced while presenting the 12 motif stimuli until two or more auditory single units were isolated. Once single units were isolated, all 12 single motifs and the set of training

motif pairs were presented pseudorandomly in blocks while the extracellular electrical activity was amplified (5,000 × gain; AM Systems), filtered (high pass, 300 Hz; low pass, 3–5 kHz), sampled (20 kHz), and and saved digitally learn more for offline analysis (Spike2; Cambridge Electronic Design). Putative action potentials in the recorded voltage traces were identified by amplitude and sorted into single units with principal components analysis on waveform shape

using Spike2 software (Cambridge Electronic Design). Only large amplitude spike waveforms that formed a clear cluster in principal component space and that had very few refractory period violations were considered to be single units. In our sample, 99.3% (133/134) of all (Wide Spiking+Narrow Spiking) neurons had no refractory violations (interspike intervals of less than 1 ms) and one neuron had a single violation, which accounted for less than 0.005% of all measured ISIs for that neuron. Since presentation of task-relevant, task-irrelevant, and novel motifs was temporally interleaved, none of the effects reported here can be due to changes in neuron isolation or changes in anesthetic state. Because the recording sites on each multichannel array were only 50 μm apart, stereotrode sorts were used to further improve spike-sorting quality. All but one of the WS neuron pairs analyzed here were recorded from different electrode channels on the multichannel arrays. Omitting the one pair recorded from the same channel does not alter the main results. Only neurons that were driven by at least one motif were used in subsequent analyses. All further analysis was performed using custom-written MATLAB (MathWorks) software.

, 2011) such that Olig2 function (and presumably phosphorylation)

, 2011) such that Olig2 function (and presumably phosphorylation)

is irrelevant in a p53 null context. Together, these findings indicate that Olig2 phosphorylation at the triple serine motif is present in human glioma and regulates tumor growth in a genetically relevant mouse orthotopic model. What is the molecular mechanism that links Olig2 phosphorylation to neurosphere growth Ion Channel Ligand Library cell line and formation of malignant gliomas? A companion paper by Mehta et al. (2011) describes an intrinsic oppositional relationship between Olig2 and p53. Put briefly, Mehta et al. (2011) show that expression of Olig2 suppresses the posttranslational acetylation of p53, which is known to be required for optimum transcriptional functions (Barlev et al., 2001 and Dornan et al., 2003). Concurrent with hypoacetylation, the interactions of p53 with promoter/enhancer elements of its stereotypical target genes (e.g., p21,·Bax, Mdm2) are much attenuated in wild-type neural progenitors relative to their Olig2-null counterparts. Accordingly, p53-mediated biological responses to genotoxic damage

are suppressed by Olig2. Experiments summarized in Figure 7 show that this oppositional relationship between Olig2 and p53 is regulated by the phosphorylation state of the triple serine motif. Wild-type and also phosphomimetic Olig2 suppress the radiation-induced increase in both total p53 (Figure 7A) and acetylated p53 (Figure 7B). Likewise, wild-type and phosphomimetic Olig2 suppress radiation-induced expression of the canonical p53 target gene p21 (Figure 7C, inset). Concurrent with suppression of p21 expression, wild-type and phosphomimetic Olig2 promote the survival Palbociclib in vitro of irradiated neural progenitors, as noted by Mehta et al. (2011) (Figure 7C).

In marked contrast, phospho null Olig2 is deficient in all of these functions. In previous studies we have shown that basal levels of p21 expression seen in cycling neural progenitor cells are also suppressed by Olig2 (Ligon et al., 2007). As shown in Figure 8A (inset), wild-type and phosphomimetic Olig2 suppress basal levels of p21 protein, whereas phospho null Olig2 shows little or no effect. The phospho Olig2-mediated suppression of p21 protein is exerted largely at transcriptional level, as indicated by diminished expression of p21 mRNA ( Figure 8A). Expression of a p21 luciferase reporter gene is likewise controlled by Olig2 in a phosphorylation ADAMTS5 state-dependent manner ( Figure S8). This suppression of basal state p21 mRNA reflects, at least in part, phospho Olig2-regulated changes in the amount of p53 that is associated with promoter/enhancer elements of the p21 gene ( Figure 8B). The differential loading of p53 onto p21 promoter enhancer element is nuanced but statistically significant and also in good accord with the basal state levels of acetylated p53 seen in Figure 7B. On a final note, the phosphorylation state-dependent effects of Olig2 on neurosphere proliferation noted in Figure 1 are completely dependent on p53 status.