The stack was then flattened into a maximum z-projection

The stack was then flattened into a maximum z-projection Selleckchem BI-2536 using ImageJ. For quantifications presented in Figure 2, lengths were measured within the original confocal z-slices using the line tool in Volocity. Statistical tests were performed using InStat (GraphPad). We would like to thank G. Banker (pBa-Kif5c560-YFP) and D.L. Stemple (lamα1 morpholino) for the generous gift of reagents; H. Lynn and C.J. Wilkinson for molecular cloning; and A. McNabb, T. Dyl, and K.L. Scott for fish maintenance. We are grateful to C.-B. Chien,

C. Norden, P. Jusuf, and K.M. Kwan for suggestions on the manuscript. W.A.H. conceived of and supervised the study. O.R. performed and analyzed all of the experiments presented. O.R and W.A.H. designed the experiments and wrote the manuscript. L.P. helped in the creation of the Centrin-GFP transgenic, and with the initial blastomere transplantation experiments. F.R.Z. performed the preliminary in vitro Lam1 bead and Centrin-GFP experiments. O.R. is a member of the Wellcome Trust programme in Developmental Biology, and is also funded

by the Cambridge Overseas Trust. This work was supported by a Wellcome Trust Programme Grant to W.A.H. “
“Neurons extend processes over long distances during Selleck DAPT development, establishing complex yet precise connections to achieve mature neuronal functions. During this process growing neuronal processes recognize and interpret numerous cues as they navigate to their appropriate targets (Raper and Mason, 2010 and Tessier-Lavigne and Goodman, 1996). In both vertebrates and invertebrates,

longitudinal neural tracts extending along the anterior-posterior axis within the nerve cord serve to exchange and integrate information between different body segments and the brain. To establish these tracts, developing neurites must extend across segmental boundaries, already often fasciculating with related neurites from a myriad of possible partners in adjacent segments. In addition, longitudinal pathways often receive neural input from sensory afferents and other local interneurons critical for processing specific sensory information and modulating appropriate motor responses. These two aspects of longitudinal tract assembly could be intrinsically linked to better achieve select targeting of neuronal projections that belong to the same circuit. Cellular experiments in both invertebrates and vertebrates demonstrate the importance of contact with pioneer neurons for the establishment of continuous rostral-caudal neuronal pathways (Goodman et al., 1984, Kuwada, 1986 and Wolman et al., 2008). Genetic analyses in the Drosophila embryonic CNS reveal molecular mechanisms governing important aspects of longitudinal pathway organization within the nerve cord.

In order to investigate the mechanism of maintenance of ΔΨm, a se

In order to investigate the mechanism of maintenance of ΔΨm, a series of mitochondrial toxins were applied and their effects on ΔΨm were observed. All control cells and VCP KD SH-SY5Y cells showed no significant response to the F1F0-ATP synthase inhibitor oligomycin (0.2 μg/ml), while subsequent inhibition of complex I by rotenone (5 μM) caused a rapid loss of potential ( Figure S2A). However, application of oligomycin to patient fibroblasts carrying VCP mutations resulted in a modest depolarization, suggesting that complex V may be partially working in reverse mode

in these cells, in order to maintain the ΔΨm ( Figure S2B). Application of rotenone (5 μM) to inhibit complex I then generated a strong depolarization. Complete depolarization was assessed in all cell models by addition of the PS-341 concentration mitochondrial uncoupler carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) (1 μM) ( Figure S2B). Taken together, these data suggest that ΔΨm is mainly maintained by respiration in VCP-deficient cells. The redox state of NADH or FAD reflects the activity of the mitochondrial electron transport chain (ETC) and the rate of substrate supply. We measured the basal levels of NADH (substrate for the ETC complex I) and FAD autofluorescence and generated the “redox indexes” by expressing basal NADH or FAD levels as a percentage of the difference

between the maximally oxidized and maximally reduced signals. The maximally oxidized signal is defined as the response to 1 μM FCCP that stimulates maximal respiration, while the maximally reduced signal is defined as the response to 1 mM Torin 1 research buy NaCN that fully inhibits respiration. Figure 2A shows average traces for NADH autofluorescence in untransfected, SCR, and VCP KD SH-SY5Y cells. The NADH redox index generated

was those significantly lower in transient VCP KD SH-SY5Y cells (17% ± 2%, n = 8) compared to control untransfected (28% ± 3%, n = 8) and SCR-transfected (29% ± 3%, n = 8) cells ( Figure 2B), indicating a depletion of NADH under basal conditions. NADH redox index in patient fibroblasts was also lower than in the age-matched controls (patient 1 = 49% ± 7%, n = 9; patient 2 = 48% ± 8%, n = 8; patient 3 = 43% ± 9%, n = 10; control 1 = 84% ± 10%, n = 7; control 2 = 66% ± 7%, n = 7; control 3 = 83% ± 9%, n = 8) ( Figure 2C). We then measured the FAD autofluorescence in SH-SY5Y cells. Figure 2D shows average traces for FAD in untransfected, SCR, and VCP KD SH-SY5Y cells. The generated FAD redox index was significantly higher in transient VCP KD SH-SY5Y cells (75% ± 13%, n = 4) compared to control untransfected (21% ± 5%; n = 4) and SCR-transfected (32% ± 4%; n = 4) cells ( Figure 2E). We were unable to measure the FAD redox state in fibroblasts due to the very low level of FAD autofluorescence in these cells.

(2011) reached a similar conclusion concerning the effect of Sema

(2011) reached a similar conclusion concerning the effect of Sema3A on axon development in the Xenopus model system. In vitro Sema3A treatment resulted in the conversion of Androgen Receptor antagonist neurites that would normally form axons into dendrites ( Nishiyama et al., 2011). The Nishiyama study

adds an additional piece to the puzzle by suggesting that Sema3A-induced cGMP signaling is able to induce expression of functional Cav2.3 channels ( Nishiyama et al., 2011). Expression of functional Cav2.3 channels was required for suppression of axonal development in vitro and for the appropriate acquisition of dendritic markers in vivo. Therefore, Sema3A may signal through a cGMP-mediated insertion of Cav2.3 channels to promote dendrite specification in addition to inhibiting axon specification. Is the position of the axon purely dictated by a lack of inhibitory factors, or is there

an extrinsic signal specifying axonal fate? Although BDNF could promote axon growth in vitro (Shelly et al., 2007 and Shelly et al., 2010), in vivo evidence supporting its role in axon specification remains to be shown. Other signaling molecules have somewhat stronger support. Netrin is required for the appropriate outgrowth of the only neurite of the HSN neuron in C. elegans ( Adler et al., 2006). In the absence of netrin (unc-6) or its receptor (unc-40), neurite outgrowth was delayed, and the process that did eventually emerge from the cell body was misguided ( Adler et al., 2006). Signaling through the TGF-β receptor, OSI-744 order TβR2, has recently been shown to be necessary for pyramidal axon formation in vivo ( Yi et al., 2010). A growing number of studies support the model that extrinsic signaling molecules can dictate the axon-dendrite polarity axis (Figure 1). While some molecules may promote axon outgrowth at the appropriate location, others such as Sema3A may Adenosine promote dendrite formation by inhibiting acquisition

of axonal fate. Other signals may be needed to help dictate appropriate dendrite outgrowth. The ability of neurons to break symmetry in vitro and the relatively low penetrance of in vivo phenotypes raise the possibility that these extrinsic cues may be redundant, with the internal polarizing pathways able to utilize a variety of extrinsic signals to dictate axon and dendrite outgrowth. As the signaling pathways regulating axon-dendrite polarity in vivo come into focus, it remains to be determined how these signals are spatially restricted or localized to effectively establish their cellular functions. Nonetheless, the study by Shelly et al. (2011) provides a novel framework within which to address these unresolved issues. “
“Stress plays a prominent role in modern life. The effects of war, terrorism, political upheaval, economic uncertainty, climate change, parental mistreatment, and bullying can be profoundly stressful.

The detailed compositions of all pipette solutions, as well as fu

The detailed compositions of all pipette solutions, as well as further details concerning patch pipette resistances, series resistance (Rs) during recording and off-line Rs compensation of EPSC and IPSC traces, are given in Supplemental Experimental Procedures. Data analysis was performed using the IgorPro software. Rates of transmitter release were determined by EPSC deconvolution analysis using routines written in IgorPro by Neher and Sakaba (2001). PD0332991 nmr Data are reported as average ± SEM values, and statistical significance was evaluated using unpaired, two-tailed t test with Welch’s correction (Prism software). Statistical significance

was accepted at p < 0.05. Asterisks above brackets in data bar graphs indicate the level of statistical significance (*p < 0.05; **p < 0.01; and ***p < 0.001). A bracket without symbol indicates p > 0.05 (not significant). The methods for immunohistochemistry and in situ hybridization, as well as DiI tracing and acoustic labeling experiments, are given in Supplemental Experimental Procedures. We thank Jessica Dupasquier, Coraly Pernet, Heather Murray, and Nicolas Rama for expert PF-02341066 concentration technical assistance, Enida Gjoni for help with LSO recordings, and Jean-Pierre Hardelin for critical comments on the manuscript. This research

was supported by a Marie Curie post-doctoral fellowship (IEF-235223-Calyx-MMFF to N.M.), the Swiss National Science Foundation (SNF; Sinergia grant CRSI33_127440/1 to R.S.), the National Center of Competence in Research (NCCR) of the SNF “Synaptic Bases of Mental Disease,” the Fondation pour recherche médicale (FRM; to A.C.), the Association Française contre les Myopathies (AFM, ASS-SUB06-00123; to A.C.), the Labex lifesenses (to A.C.), and the Agence Nationale de la Recherche (ANR-2011 BSV 40091; to A.C.) “
“Animals coordinately adjust their behaviors in response to changes in their environment and metabolic state. Coregulated behaviors (often termed behavioral states) can persist for minutes to hours. Increased activity (or arousal) Olopatadine is associated

with fear, stress, hunger, and exposure to sexual partners (Pfaff et al., 2008). Conversely, decreased activity (or quiescence) is associated with sleep and satiety (Cirelli, 2009). Many aspects of behavior and metabolism exhibit rhythmic patterns with a periodicity of approximately 24 hr, patterns generically referred to as circadian rhythms (Allada and Chung, 2010). Daily behavioral and metabolic rhythms are accompanied by a corresponding set of circadian changes in gene expression. Circadian rhythms are dictated by a cell-autonomous clock that consists of a transcriptional feedback network that exhibits intrinsically oscillating activity. The period of this circadian clock is entrained by daily changes in light and temperature, although daily rhythms persist even in constant conditions.

As cerebral endothelial cells do not express CD4 and galactosylce

As cerebral endothelial cells do not express CD4 and galactosylceramide ( Moses et al., 1993), HIV-1 and HIV-infected immune cells use other routes to invade CNS parenchyma by using their own cell surface glycoproteins

to engage the adsorptive endocytosis mechanism on cerebral endothelial cells in order to LY2109761 mw cross over the barrier formed by these cells, thus infiltrating and infecting the CNS ( Banks et al., 1997). Moreover, the poliovirus (PV) has been shown to cross the BBB via two mechanisms, either by exploiting the receptor-mediated endocytosis via the CD155 receptor (i.e., PV receptor, PVR) or by inducing caveolin-dependent endocytic mechanism at cerebral endothelial cells ( Coyne et al., 2007). Moreover, it has been proposed that BBB breakdown could contribute to epilepsy pathogenesis. As such, BBB failure has been proposed to take place early in epilepsy pathogenesis, which causes the entry of blood-borne molecules into the brain, namely albumin (van Vliet et al., 2007). Albumin extravasation triggers astrocytes’ dysfunction by activating transforming growth factor β (TGFβ)-receptor Cyclopamine solubility dmso II (TGFβ-RII), therefore exacerbating BBB dysfunction and initiating epileptic activity

and seizures (Friedman et al., 2009). This epileptic activity has been suggested to induce long-lasting innate immunity response and to promote infiltration of lymphocytes into the brain (Vezzani, 2005). A complex immune reaction is engaged in the CNS in response to mechanical or ischemic traumas, viral or bacterial infections, or the accumulation toxic proteins. We discuss here the molecular bases of the innate immune response in the CNS. In cases of infections, traumas, and pathological conditions, the CNS comes into contact with small protein patterns

that regulate innate immunity, found in large numbers of microorganisms (Figure 2). Such patterns (coined PAMPs for pathogen-associated molecular patterns and DAMPS for danger-associated molecular patterns) include proteins from Carnitine dehydrogenase bacterial membranes such as peptidoglycans, intracellular proteins such as heat-shock proteins, and nonprotein products such as ATP and urea and nucleic acid patterns such as nonmethylated CpG-containing DNA, dsRNA, and ssRNA (Kumar et al., 2011). These are recognized by pattern recognition receptors (PRRs), of which three major families exist: Toll-like receptors (TLRs), Nod-like receptors (NLRs), and RIG1-like receptors (RLRs). The role for these receptors in the CNS has been mostly studied in microglia, but astrocytes, oligodendrocytes, endothelial cells, and even neurons express functional levels of some of these receptors (Hanamsagar et al., 2012). The engagement of such receptors results in the induction of specific pathways and the release of specific cytokines that play a role in resolving the injury. There are 11 TLR family members in humans and 13 in mice.

It is important to test how sensitive BOLD connectivity is to osc

It is important to test how sensitive BOLD connectivity is to oscillatory

frequencies lower than gamma because it is not necessary for local computation and large-scale communication to recruit the same frequencies of oscillatory activity. Rather, low frequencies may be advantageous and commonly used for interactions between distant brain areas (Fujisawa and Buzsáki, 2011; Siegel et al., 2012). A number of electrophysiological studies have demonstrated that brain oscillations show statistically INCB024360 cost nested coupling, with low frequencies modulating high frequencies (Buzsáki and Wang, 2012; Jensen and Colgin, 2007; Schroeder and Lakatos, 2009). Given that different oscillations are associated with different spatiotemporal scales (Buzsáki and Draguhn, 2004; von Stein and Sarnthein, 2000), cross-frequency coupling may integrate information transmission over a large-scale network with local cortical processing (Canolty Selleck Gemcitabine and Knight, 2010). We thus hypothesized that (1) BOLD functional connectivity predominantly reflects low-frequency neural interactions between remote brain areas (e.g., alpha [8–13 Hz] and theta [4–8 Hz]); (2) low frequencies modulate local high-frequency activity (e.g., gamma), which

predominantly reflects BOLD signals from an individual area; and (3) such cross-frequency coupling links BOLD correlations in distributed network nodes to local BOLD activations. To test our hypotheses, we first

mapped out thalamo-cortical networks (i.e., network defined as a set of interconnected brain regions) derived Astemizole from BOLD signals acquired from macaque monkeys. Given that task-free fMRI studies have involved various experimental conditions in humans (free gaze, eyes closed, and fixation) and monkeys (free gaze and anesthesia), our study incorporated three experimental conditions to allow generalization and ready comparison with the literature: a task-free, free-gaze condition, defined as resting state here; a fixation task; and anesthesia. We focused on a thalamo-cortical visual network constituted by the lateral intraparietal area (LIP), the temporal occipital area (TEO), area V4, and the pulvinar, which has been well studied in terms of its anatomical connectivity (e.g., Felleman and Van Essen, 1991; Saalmann et al., 2012; Shipp, 2003; Ungerleider et al., 2008). After verifying BOLD correlations across our visual network, we performed simultaneous electrophysiological recordings from the same four network areas and measured their functional connectivity based on LFPs. We included a thalamic nucleus, the pulvinar, in our study because the limited evidence available suggests that the thalamus makes an important contribution to cortical oscillations (Hughes et al., 2004; Saalmann et al., 2012; Steriade and Llinás, 1988). We used a combination of fMRI retinotopic mapping (Arcaro et al.

, 2008 and Noor et al , 2010)

and amyotrophic lateral scl

, 2008 and Noor et al., 2010)

and amyotrophic lateral sclerosis susceptibility gene (Cronin et al., 2008 and van Es et al., 2008). DPP6 enhances the opening probability and single-channel conductance of Kv4 channels and increases channel surface expression in heterologous systems (Kaulin et al., 2009, Maffie and Rudy, 2008 and Nadal OSI-744 datasheet et al., 2003). A ternary complex of Kv4, DPP6, and Kv channel-interacting proteins (KChIPs) is thought to underlie the native A-type K+ current in CA1 neurons (Kim and Hoffman, 2008 and Maffie and Rudy, 2008). To investigate the influence of DPP6 in a native system, we generated conditional DPP6 knockout (DPP6-KO) mice (DPP6fl/fl). These mice were crossed to a Cre deleter strain expressing Cre recombinase in the germline to generate DPP6 null alleles (DPP6-KO mice). In patch clamp recordings from wild-type (WT) mouse CA1 hippocampal dendrites, we observed that the density of A-type currents increased with distance from the soma, as found previously for rats (Hoffman et al., 1997). However, in dendritic recordings from DPP6-KO mice, the A-current distribution in CA1 primary apical dendrites was altered so

that the density was, on average, the same throughout the primary apical dendrite. Accordingly, dendritic excitability was enhanced in CA1 dendrites from acute hippocampal MK-1775 clinical trial slices prepared from adult DPP6-KO mice: bAPs were better able to invade distal dendrites, trains of APs were more faithfully conveyed than in recordings from WT mice, and the threshold frequency for the generation of Ca2+ spikes and long-term potentiation (LTP) was lowered in DPP6-KO dendrites. In contrast to the critical role of DPP6 in dendritic excitability, firing behavior evoked by somatic heptaminol current injections was only minorly affected in DPP6-KO CA1 recordings. In addition to establishing a role for DPP6 in generating the A-current gradient in CA1 neurons, these observations provide evidence that the enhanced dendritic A-current is particularly important for the regulation of dendritic

excitability including dendritic spiking and plasticity. We have previously shown using siRNA that acute knockdown of DPP6 moderately influences the firing patterns of hippocampal CA1 neurons in somatic recordings from hippocampal organotypic slice cultures (Kim et al., 2008). However, it is at the distal apical dendrites of CA1 neurons that A-current expression and activation prominently control excitability, and the small caliber of dendrites in cultured neurons precludes electrophysiological recordings from distal sites. Therefore, to investigate the functional significance of DPP6 in mature dendrites, we generated DPP6-KO mice (Figure 1A). DPP6-KO mice displayed a total loss of DPP6 mRNA and protein (Figures 1B–1D). The closely related family member DPP10 is not normally expressed in CA1 pyramidal dendrites (Zagha et al., 2005) and is not upregulated in these cells in DPP6-KO mice (Figure 1E).

Input resistances and time constants increase, and excitability a

Input resistances and time constants increase, and excitability also rises. The loss of functional Cv-c from dorsal FB neurons locks the cells in a high-conductance state that likely corresponds to one extreme of the normal operating range of the sleep homeostat (Figure 7). The inability of mutants to exit this high-conductance state despite intense buy Forskolin sleep pressure (Figures 2 and 7) suggests that an essential role of Cv-c is to tune the channel repertoire of sleep-control neurons. Some of the putative substrates of Cv-c, small GTPases of the Rho family (Denholm et al., 2005), have indeed been implicated in various forms of ion channel regulation. RhoA in

its active, GTP-bound, membrane-associated state modulates the conductances of delayed rectifier potassium currents (Cachero et al., 1998). Rac1 in its active state promotes the fusion of vesicles containing transient receptor potential channels and thereby increases channel densities in the plasma membrane (Bezzerides et al., 2004). These precedents illustrate the wide range of potential small GTPase substrates, cellular processes, and ion channel targets that future work will have to sift through in order to arrive at a complete molecular description

of the sleep homeostat. That said, there still remains a formal possibility that the function of Cv-c in sleep control might be divorced altogether from its catalytic Metalloexopeptidase role in the guanine nucleotide cycle of Rho family proteins. Intriguingly, independent evidence already points to the importance of ion channels in sleep control. Candidate see more genes identified in mutagenesis or small-molecule screens encode the fast delayed rectifier potassium channel Shaker ( Cirelli et al., 2005) as well as its cytoplasmic beta

subunit hyperkinetic ( Bushey et al., 2007) and its extracellular regulator sleepless (or quiver) ( Koh et al., 2008), the slow delayed rectifier potassium channel ether-à-go-go ( Rihel et al., 2010), and the voltage-gated sodium channel narrow abdomen ( Lear et al., 2005). Our discovery that ion channel modulation in sleep-control neurons lies at the core of sleep homeostasis offers a physiological context for the pursuit of these leads. Fly stocks were grown on standard media of sucrose, yeast, molasses, and agar and maintained on a 12 hr light/12 hr dark schedule. The following strains were used: cv-cMB03717, cv-cMB01956, cv-cDG20401 ( Bellen et al., 2011 and Venken et al., 2011); cv-cC524, UAS–cv-c ( Denholm et al., 2005); UAS–cv-cRNAi ( Billuart et al., 2001); UAS–CD8-GFP ( Lee and Luo, 1999); C5–GAL4 ( Yang et al., 1995); 104y–GAL4 ( Rodan et al., 2002 and Sakai and Kitamoto, 2006); C205-GAL4 ( Martin et al., 1999); 23E10–GAL4 ( Jenett et al., 2012); tubP–GAL80ts ( McGuire et al., 2003). Baseline sleep was measured as previously described (Shaw et al., 2002).

SLd is thus the relative drop in Rd at location d due to the acti

SLd is thus the relative drop in Rd at location d due to the activation of single (or multiple) steady conductance changes at arbitrary dendritic locations (see Figures S8 and S9 and related text available online for generalization to the transient case). The value of SLd ranges from 0 (no shunt) to 1 (infinite shunt) and depends on the particular dendritic distribution of gis. For example, SLd = 0.2 implies

that the inhibitory synapse reduced the input resistance at location d by 20%, which is also the relative drop in the steady voltage at d due to the inhibition after the injection of steady current at location d. Thus, in order to characterize the effect of the inhibitory shunt in the most general way, it is natural to ask how much increase in excitatory current is required in order to exactly counter effect the shunting inhibition. This is exactly what GW786034 clinical trial SL implies. Note that the SL measure is applicable also for assessing the change in input resistance due to excitatory synapses that, like inhibition, exert

a local membrane conductance change. The spatial spread of SL can be solved using cable theory for arbitrary passive dendritic trees receiving multiple inhibitory synapses (see Experimental Procedures and Supplemental Information). This solution provides several new and counterintuitive results regarding the overall impact of multiple inhibitory dendritic synapses in dendrites and explains several experimental and modeling results that were not fully understood prior to the present study. We started with a geometrically Selleckchem Venetoclax simple case, whereby a single inhibitory synapse impinges on a dendritic cylinder that is sealed ended

at one side and is coupled to an isopotential excitable soma at the other (Figure 1A). The dendritic cylinder is comprised of a hotspot (Magee et al., 1995; Schiller et al., 1997, 2000; Larkum et al., 1999; Antic et al., 2010), which is modeled by a cluster of 20 NMDA synapses, each randomly activated at 20 Hz (red circle and red synapse in Figure 1A). We then searched for the strategic placement of the inhibitory synapse only that would effectively dampen this local dendritic hotspot. Using numerical simulations for the nonlinear cable model that includes the spiking soma and NMDA synapses depicted in Figure 1A, we found that when the inhibitory conductance change, gi, was placed distally (“off-path”) to the hotspot, the rate of the soma action potentials (black trace in Figure 1B) was reduced more effectively than when the same inhibitory synapse was placed proximally (“on-path”) at the same distance from the hotspot (orange trace in Figure 1B). Indeed, such asymmetry in the impact of proximal versus distal inhibition for dampening local dendritic hotspot was previously observed in vitro ( Miles et al., 1996; Jadi et al., 2012; Lovett-Barron et al.

The original model predicted

The original model predicted BAY 73-4506 supplier a decrease in the frequency of single-cell membrane-potential oscillations along the dorsoventral axis of MEC, in parallel with the decrease in the spatial frequency of the grid (O’Keefe and Burgess, 2005). Such a frequency change was subsequently demonstrated in whole-cell patch-clamp recordings of medial entorhinal layer II neurons (Giocomo et al., 2007). Moreover, consistent with the prediction that oscillations are key to generating

stable grid cell representations, loss of the global theta rhythm by medial septum inactivation has been shown to result in loss of periodicity in the firing locations of grid cells (Brandon et al., 2011 and Koenig et al., 2011). As predicted, the frequency of the field theta rhythm has been found to be more sensitive to changes in the rat’s running speed in dorsal compared to ventral MEC (Jeewajee et al., 2008), and ventral MEC cells have been reported to fire only on every other theta peak (theta skipping) (Deshmukh et al., 2010), in agreement with an oscillatory-interference model implemented in a resonant network (Zilli and Hasselmo, 2010). It should be noted, however, that these experimental results can in principle also learn more be obtained by mechanisms other than oscillatory interference. Recently, multiple criticisms of the

first generation of oscillatory-interference models have been raised. For example, several papers have criticized the oscillatory-interference approach for modeling biological oscillators as perfect sinusoids (Giocomo and Hasselmo, 2008a, Welinder et al., 2008 and Zilli et al., 2009). In contrast to the modeled oscillations, in vitro slice recordings indicate that membrane-potential oscillations show a high degree of noise (Dudman and Nolan, 2009 and Zilli et al., 2009), variance in frequency (Giocomo

and Hasselmo, 2008a), and significant attenuation in high-conductance conditions, which may occur during realistic in vivo levels of synaptic input (Fernandez and White, 2008). Computational simulations indicate that accumulating noise interferes with the grid pattern. The rate at which a grid cell’s Terminal deoxynucleotidyl transferase spatial pattern drifts from its correct position can be calculated based on the variance of the oscillator (Welinder et al., 2008 and Zilli et al., 2009). The measured variance in persistent spiking neurons and membrane-potential oscillations is not able to keep the grid pattern stable for more than a few seconds (Welinder et al., 2008 and Zilli and Hasselmo, 2010), whereas the pattern is maintained for minutes in vivo ( Hafting et al., 2005). In addition, criticism has focused on the assumption that multiple, separate oscillations combine in the soma while maintaining independence in the dendrites (Remme et al., 2009).