An important aspect of understanding DAPT purchase a pathogenic repeat expansion focuses on its stability. Preliminary evidence suggests that the C9ORF72 hexanucleotide repeat expansion may be unstable. First, minor anticipation has been noted in pedigrees that originally identified the locus with earlier generations being relatively unaffected by disease, perhaps reflecting expanding repeat number over successive generations ( Vance et al., 2006). Interestingly, anticipation was not observed within the five families

in which we found the hexanucleotide repeat expansion (see Figure 1). Second, although there was strong concordance between the presence of the chromosome 9p21 founder risk haplotype and the presence of the hexanucleotide expansion in an individual, the expansion was also present

in ALS cases that did not carry this haplotype. These data are consistent with the expansion occurring on multiple occasions on multiple haplotype backgrounds. Taken together, these observations suggest that the C9ORF72 repeat region has some degree of instability. This instability may be particularly relevant for sporadic ALS, where the apparent random nature of the disease in the community could be a consequence of stochastic Talazoparib supplier expansion in the number of repeats. It is noteworthy that a sizeable proportion of the Finnish ALS cases that carried the repeat expansion was clinically classified as sporadic. In summary, our data demonstrate that a massive hexanucleotide repeat expansion within Calpain C9ORF72 is the cause of chromosome 9p21-linked ALS, FTD, and ALS-FTD. Furthermore, this expansion accounts for an unprecedented

proportion of ALS cases in Finland and in familial ALS cases of European ancestry, and it provides additional evidence supporting the role of disrupted RNA metabolism as a cause of neurodegeneration. We studied a four-generation Welsh family (GWENT#1) in which 9 individuals had been diagnosed with ALS and/or FTD and were known to share the chromosome 9p21 risk haplotype. The pedigree of this family is shown in Figure 1A, and the clinical features have been previously reported (Pearson et al., 2011). DNA samples were available from four individuals of generation IV who had been diagnosed with ALS and/or FTD. Flow-sorting of chromosome 9 was performed on lymphoblastoid cell lines from an affected case ND06769 (IV-3, Figure 1A) and a neurologically normal population control ND11463 at Chrombios GmbH (http://www.chrombios.com) using a FACS Vantage cell sorter (BD Biosciences, Franklin Lakes, NJ, USA). We also analyzed an apparently unrelated six-generation Dutch ALS/FTD family (DUTCH#1, Figure 1B), in which linkage and haplotype analysis showed significant linkage to a 61 Mb region on chromosome 9p21 spanning from rs10732345 to rs7035160 and containing 524 genes and predicted transcripts.

Others have proposed that serotonin is primarily involved in the inhibition of thoughts and actions associated

with aversive outcomes (Daw et al., 2002), including the process of heuristically disregarding unpromising branches of decision trees (Dayan and Huys, 2008; Huys et al., 2012). According to this view, depressed individuals would expect a lower rate of reward from their actions, because insufficient serotonin would expose the negative outcomes of potential actions that would be normally subject to pruning. More research is needed, however, for understanding the nature of neural processes mediating the effects of various neuromodulators, such as serotonin, during decision making. find more Autism is a neurodevelopmental disorder, characterized by impaired social cognition, poor communicative abilities, repetitive behaviors, check details and narrow interests (Geschwind and Levitt, 2007). In particular, individuals with autism are impaired in their ability to make inferences regarding the intentions and beliefs of others, namely, theory of mind, as reflected in their poor performance with the false-belief task (Baron-Cohen et al., 1985;

Frith, 2001). Such reduced abilities to mentalize the intentions of others might underlie differences in the strategies of autistic individuals and control subjects during socially interactive decision-making tasks. For example, children with autism tend to offer a smaller amount of money as proposers during the ultimatum game, and they are also more likely to accept even very small offers as responders (Sally and Hill, 2006). In crotamiton addition, whereas control subjects donated more money to charity in the presence of observers, this effect was absent in individuals with autism (Izuma et al., 2011). Autistic individuals are also impaired in their abilities to infer mentalizing strategies of others (Yoshida et al., 2010). Some of these social impairments in autism are ameliorated by oxytocin, but precisely how oxytocin influences

affective and social functions of the brain remains poorly understood and must be more carefully characterized (Yamasue et al., 2012). Although autism has heterogeneous etiology, abnormality in the long-range connections between different association cortical areas is often considered important (Geschwind and Levitt, 2007). Such anatomical changes might underlie reduced inter-hemispheric synchronization in neural activity recorded from toddlers with autism (Dinstein et al., 2011). Anatomical and physiological abnormalities in autism might produce their most prominent effect in the domain of social cognition. Consistent with the possibility that the default network might be important for mental simulation in social contexts, the default network is hypoactive in individuals with autism (Figure 4B; Kennedy et al., 2006).

To detect the loci of MMPs activity within invading H9c2 cells, an in situ zymography approach was employed ( Galis et al., 1995). Briefly, after incubation with T. theileri for one hour, H9c2 cells were washed with PBS five times, and then incubated with DQ-labeled gelatin (Invitrogen) substrate solution (20 μg/ml DQ-gelatin, 50 mM Tris, pH 6.8, 50 mM NaCl, 20 mM CaCl2) for 2 h at 37 °C in the dark. After the substrate solution was washed off, slides were incubated in 4% PFA for 10 min, washed with PBS, mounted with DAPI, and photographed with identical exposure settings using a laser confocal microscope (FV1000-D, Olympus). After fixation with 4% paraformaldehyde (PFA)

in PBS for 5 min, chamber slides with attached cells were washed three times in PBS. Nonspecific immunoglobulin EPZ-6438 nmr binding sites were blocked with www.selleckchem.com/EGFR(HER).html 5% BSA for 30 min at room temperature, and then cells were incubated with first antibody: rabbit anti-TWTth1 polyclonal antibody, MAP1LC3A antibody (ab64123, Abcam), or TGF-β pan specific polyclonal antibody (AB-100-NA, R&D Systems) with Tris-buffered saline-Tween 20 (TBS-T) containing 2% BSA at 4 °C

overnight. The sections were then incubated with FITC conjugated anti-rabbit IgG for 1 h at room temperature, followed by washing, mounting and examination by laser confocal microscopy. Analysis of transcripts of the TGF-β1 gene by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed as described in our previous study (Cheng et al., 2010). For tracing MTMR9 in live cell images, BHK, SVEC, and H9c2 cells and T. theileri were labeled with CellTracker™ Probes (Molecular Probes™) for long-term tracing: LysoTracker Red DND-99/Green DND-26 (L-7528, L-7526), and MitoTracker Red CMXRos/Green FM (M-7512, M-7514) within 30 min according to the manufacturer’s protocol (Invitrogen), followed by Hoechst 33342 (H-21492) staining for invasion assay. To identify the possible interaction between T. theileri and the host cell via the autophagic pathway,

two sets of experiments were performed. (A) After 3 h infection, cells were washed four times with PBS and fixed with 4% PFA for 10 min at room temperature. Autophagosomes were stained with anti-MAP1LC3 antibody as described in Section 2.6 above. (B) H9c2 cells were transfected in vitro with pSelect-LC3-GFP expression plasmid (psetz-gfplc3, InvivoGen) by jetPEI™ transfection reagent (PolyPlus Transfection), according to the instructions supplied by the manufacturer. For the in vitro infection assay, LC3-GFP-expressing H9c2 cells were plated onto an Ibidi 35 mm u-Dish (Ibidi, GmbH, Martinsried, Germany), at a density of 4 × 103 cells per well, and incubated overnight at 37 °C in a 5% CO2 humidified atmosphere. Before infection, cells were washed once with culture medium to remove nonadhered cells.

, 2010). Intriguingly, the AP2 interaction site in the β1-3 subunits overlaps with the binding site for the vesicular ATPase and trafficking factor NSF (Figure 1C) (Goto et al., 2005). NSF interacts with phorbol ester-activated PKCɛ. Moreover, PKCɛ phosphorylates and activates the ATPase function of NSF. PKCɛ-mediated

phosphorylation of NSF induces its translocation to the plasma membrane and to synapses and concurrently reduces the cell surface expression of GABAARs (Chou et al., 2010). PKCɛ knockout mice are less anxious and produce lower levels of stress hormone than WT mice (Hodge et al., 2002), which is the opposite of the anxious-depressive-like phenotype of GABAAR γ2 subunit heterozygous mice and therefore consistent with increased functional expression of GABAARs (Crestani et al., 1999 and Luscher et al., 2011). Therefore, pharmacological Wnt mutation inhibitors of PKCɛ activity may have therapeutic potential for the treatment of neuropathological conditions that involve deficits

in GABAergic transmission. This NSF-dependent trafficking mechanism is reminiscent of aforementioned earlier experiments conducted in heterologous cells, showing phorbol ester-induced and PKC and clathrin-mediated endocytosis Cabozantinib research buy of GABAARs from the plasma membrane by a mechanism that is independent of GABAAR phosphorylation (Chapell et al., 1998 and Connolly et al., 1999). PKCɛ is one of seven PKC isozymes activated by phorbol esters. It therefore seems likely that PKCɛ contributes to phorbol ester-induced endocytosis of GABAARs. However, one might predict that PKCɛ and NSF-dependent endocytosis of GABAARs is counteracted by the aforementioned PKC-βII-mediated phosphorylation of β subunits, which limits endocytosis of GABAARs. Consistent with multiple PKC and PKA-regulated modes of GABAAR trafficking, these kinases can have cell-type-specific and functionally opposite

effects on mIPSC amplitudes in vivo (Poisbeau et al., 1999). A third interaction of GABAARs with AP2 involves a bipartite motif in the intracellular loop region of the γ2 subunit (Figure 1C). It consists Dipeptidyl peptidase of a 12 amino acid basic domain that is homologous to the AP2 binding site in β subunits and a more C-terminal γ2-specific YGYECL motif (Smith et al., 2008). These two domains interact cooperatively with separate domains in the μ2 subunit of AP2. The γ2-specific YGYECL motif is of particular interest as it exhibits high affinity for AP2 that is sensitive to phosphorylation at γ2 Tyr365/367 (Kittler et al., 2008). These residues are phosphorylated by Fyn and other Src kinase family members in vivo (Lu et al., 1999 and Jurd et al., 2010). A nonphosphorylated YGYECL peptide effectively competes with the AP2-γ2 subunit interaction, thereby increasing the GABAAR surface expression and mIPSC amplitude and showing that this site is constitutively phosphorylated in cultured neurons (Kittler et al., 2008).

In line with its strong GS.motifs.X score, Ypel5 was behaviorally regulated, with lower protein levels observed in area X of birds that sang more motifs ( Figure 8B). Our results for both Reelin and Ypel5 demonstrate expression of multiple members of their respective signaling pathways in area X, with behavioral regulation of each. As further validation, we detected protein signals within area X consistent with expression of Transient Receptor Potential Vanilloid Type 1 (Trpv1), a capsaicin receptor. We selected Trpv1 for validation because of its high MM and selleck screening library GS.motifs.X, and its identification as an ion channel positively

selected for in the songbird lineage (Figure S7B; Warren et al., 2010). TRPV1 is in the dark green Smoothened antagonist and salmon singing-related modules (one probe in each; dark green: MM = 0.85, GS.motifs.X = −0.77; salmon: MM = 0.81, GS.motifs.X = −0.51;

Table S2) and has been linked to endocannabinoid signaling pathways in the mammalian basal ganglia ( Musella et al., 2009 and Maccarrone et al., 2008). Cannabinoid exposure during zebra finch development interferes with song learning ( Soderstrom and Tian, 2004), potentially through synaptic plasticity mechanisms such as modulation of glutamatergic synapses onto medium spiny neurons in area X ( Thompson and Perkel, 2011) and altered area X FoxP2 expression ( Soderstrom and Luo, 2010). In keeping with its strong GS.motifs.X score, we observed lower levels of Trpv1 signal in birds that sang more motifs ( Figure S7B). These findings provide additional biological and literature-based validation of our WGCNA. To our knowledge, this study represents the first identification of basal ganglia gene coexpression networks specialized for vocal behavior, and the first use of

WGCNA to link coexpression modules to a naturally occurring, procedurally learned behavior. We found ∼2,000 genes within the song-specialized striato-pallidal area X, but not in VSP, that were significantly coupled to singing, most of which were members of one of five distinct singing-related modules. MYO10 The three song modules (blue, dark green, orange; Figure 3) were unique to area X, and a given module’s singing-relatedness was highly predictive of its preservation outside of area X, i.e., the more related to singing, the less preserved (Figure 4). The VSP is active during singing, as indicated by IEG expression (Feenders et al., 2008), and we found gene expression levels in VSP and area X to be remarkably similar during singing (Figure 5). Thus, the regional differences we observed in network structure are probably not due to differences in expression levels, and the singing-related modules in area X are probably not a general product of neural activity, but instead reflect area X-specific singing-driven gene regulation patterns.

, 2007), but may not have the ability to support DRD2 signaling. Although WT-GHSR1a and S123A-GHSR1a and M213K-GHSR1a all have identical basal activity, of the three, only WT-GHSR1a coexpression with DRD2 mobilizes Ca2+ in response to dopamine (Figure 4A). By direct contrast, coexpression selleck kinase inhibitor of DRD2

with the basally inactive mutant produces a modest increase in Ca2+ mobilization in response to dopamine (Figure 4A). These results illustrate a lack of correlation between dopamine-induced release of intracellular Ca2+ and GHSR1a basal activity and are consistent with allosteric interactions between GHSR1a and DRD2. Agonist activation of GHSR1a in HEK293 cells results in coupling to Gαq (Smith et al., 1997). Therefore, if modification of DRD2 signaling by GHSR1a is caused by GHSR1a basal activity, ablating Gαq expression should block DRD2-mediated mobilization of Ca2+ by dopamine. When Gαq siRNA is expressed with GHSR1a and DRD2 dopamine-induced Ca2+ signaling is not suppressed (Figure 4B, left panel), whereas ghrelin-induced Ca2+ release is significantly reduced (Figure 4B, right panel). To ensure that ablating Gαq suppresses GHSR1a basal activity, we deliberately overexpressed GHSR1a to produce detectable basal activity as measured

by IP1 production. Coexpression of Gαq siRNA, EGFR inhibitor but not control siRNA, suppresses IP1 production to control levels (Figure S2A). Also, overexpression of Gαq protein does not increase dopamine-induced Ca2+ mobilization (Figure S2B). The PKC inhibitor, BisI, also does not reduce dopamine-induced Ca2+ mobilization (Figure S2C). These data provide evidence that modification of DRD2 signaling by GHSR1a is independent of GHSR1a basal signaling through Gαq and PKC. Functional crosstalk between receptors that depends on basal activity of a Gαq-coupled receptor is indicated when acute preactivation (3 min) with an agonist of the and basally active receptor synergistically increases the agonist response of the protomer partner (Rives et al., 2009). In the case of GHSR1a and DRD2, preincubation with ghrelin for 3 min has no effect on the amount of Ca2+ released in

response to dopamine (Figure S2D). Likewise, if dopamine-induced Ca2+ production is explained by potentiation of GHSR1a activity by DRD2, activation of DRD2 prior to ghrelin treatment would potentiate ghrelin-induced Ca2+ mobilization. However, this is not the case; simultaneous addition of ghrelin and dopamine results in additive Ca2+ accumulation (Figures S2E and S2F). Our collective results argue that dopamine-induced Ca2+ release is independent of GHSR1a basal activity and crosstalk between signal transduction pathways. An alternative mechanism is that GHSR1a-induced modification of canonical dopamine-DRD2 signal transduction is a consequence of allosteric modification of DRD2 signal transduction caused by formation of GHSR1a:DRD2 heteromers.

5–4 Hz) EEG with no fluctuation in EMG. REM sleep was determined by low-amplitude and high-frequency EEG (similar to wake stage, but with rhythmic theta waves at 7–9 Hz) with low-amplitude

EMG. REM theta EEG power was analyzed with fast Fourier transform for band frequencies between 4–9 Hz. Sleep deprivation was initiated from ZT 0 for 6 hr with gentle handling. Mice were tested for spatial learning and memory using a Morris water maze as described with several modifications (Han et al., 2010). Mice were allowed to swim (1 min) during the training period (4 trials/day for 5 days) and then allowed to rest on the platform. During the examination day, mice were randomly placed in the three nontarget quadrants and allowed to swim for 1 min. For electrophysiology, hippocampal slices (∼400 μm) were processed and recordings obtained as described (Foster et al., 2008) (see Temozolomide order Supplemental Experimental Procedures). Mice (2–5 months) were also tested for seizure susceptibility after injection (40 mg/kg) with pentylenetetrazol. After injection, the mice were placed in an observational area for 60 min and the time of onset of convulsive behavior and nature and severity

of the convulsion were scored according to a modified Racine scale (Lüttjohann et al., 2009). For splicing microarrays and RNA-seq, hippocampal RNAs were obtained from Mbnl2+/+ and Mbnl2ΔE2/ΔE2 mice (2–3 months, n = 3 each). Splicing microarray analysis was performed as described ( Du et al., 2010) with modifications (see Supplemental Experimental Procedures). For RNA-seq, RNAs were purified and sequencing libraries were constructed using the www.selleckchem.com/Akt.html mRNA-Seq 8-Sample Prep Kit according to the manufacturer’s protocol (Illumina).

Libraries were sequenced (40 cycles, both ends) using an Illumina Genome Analyzer IIx. Raw sequence reads were mapped back to the mouse reference genome together with a database of annotated exon junctions compiled from mouse, human, and rat mRNA/EST data. CLIP was performed as reported ( Jensen and Darnell, 2008) with modifications (see Supplemental Experimental Procedures). Temporal cortex and cerebellar autopsy tissues (12 DM1 patients, 9 disease controls) were analyzed (Table S5). This research was approved by the Institutional Ethics Committee and written informed from consent for specimen research use was obtained from all patients. RNA was extracted using the ISOGEN procedure (Nippon Gene) and cDNA was synthesized using 1–3 μg of RNA. Random hexamers and cDNA equivalent to 20 ng RNA was PCR amplified for initial denaturation at 94°C for 10 min and 35 cycles (94°C for 30 s, 55°C for 30 s, and 72°C for 30 s) (Table S6). PCR products were analyzed by capillary electrophoresis (Hitachi Electronics). The percentage of each peak was obtained by dividing each signal by the total signal and statistical analysis was performed using the Mann-Whitney U test.

We scaled the excitatory synaptic amplitude by a factor of 0.8–1.2, while keeping the inhibitory response amplitude unchanged (see Figure 4E). Figure 5F shows the frequency tuning curves of peak Vm responses at different excitatory scaling factors. To derive spiking response SCR7 from the peak Vm response, we utilized a power-law function in describing the relation between Vm and spike rate (Atallah et al., 2012, Liu et al., 2011, Miller and Troyer, 2002 and Priebe, 2008) (see Experimental Procedures). As shown in Figure 5G, the

scaling of excitatory response amplitudes resulted in negligible changes in the shape of spike tuning, although the spike rate could be modulated by as much as 50%. Within the experimentally observed range of changes of spike rate (0.4- to 1.4-fold, see Figure 1D), excitation was scaled within a range of 0.78- to 1.12-fold, and spike tuning width only varied between a narrow range of 0.93- to 1.03-fold (Figure 5H). Similar, as previously reported (Atallah et al., 2012), scaling of inhibition can also achieve an approximate gain control of spike responses (Figure 5I). The gain modulation by scaling excitation was not affected much by the inhibitory tuning shape, as similar effects on spike tuning were achieved under inhibition cotuned with excitation, more broadly tuned than excitation, or inhibition with

a flat tuning (Figure 5J). Previous studies have demonstrated that the amplitude of binaural spike response

can be modulated by interaural GSK1120212 purchase level/intensity difference (ILD), a spatial location cue (Irvine and Gago, 1990, Kuwada et al., 1997, Li et al., 2010, Pollak, 2012, Semple and Kitzes, 1985 and Wenstrup et al., 1988). In the experiments described thus far, ILD was set as zero to simulate a sound source originating on the auditory midline. To test whether a linear transformation of the contralateral into binaural spike response also applies to other binaural hearing conditions, we varied ILD to simulate different 17-DMAG (Alvespimycin) HCl sound source locations. As shown by an example cell in Figure 6A, the binaural TRFs at several different ILDs all resembled the TRF under contralateral stimulation alone. At each ILD tested, a strong linear correlation between binaural and contralateral spike responses was observed (Figures 6B and 6C). Noticeably, the gain value decreased as ILD became increasingly ipsilaterally dominant, suggesting the progressively increasing influence of ipsilaterally mediated suppression at more ipsilaterally dominant ILDs (Figure 6C). In a total of 24 similarly recorded neurons, except for two cells exhibiting enhancement, the majority of cells showed a reduction of binaural spike response with decreasing ILD (Figure 6C). The linear correlation between binaural and contralateral spike responses was similarly strong (r close to 1) at all testing ILDs and in all the cells examined ( Figure 6E), indicating that gain modulation is a general phenomenon.

, 2001) as well as a number of buy Dabrafenib cognitive and behavioral abnormalities reminiscent of symptoms in schizophrenia. This is therefore an interesting model to test specifically the neurophysiological correlates of altered cognition that may be associated with risk for the disease. The observation of enhanced firing in KO mice is consistent with convergent reports of disinhibited cortical circuits in other animal models and in patients. The critical new observation here is that awake reactivation is abolished in KO mice while basic physiology of place cells is intact. The findings indicate that

altered calcineurin in the forebrain can yield not only synaptic plasticity deficits but also disinhibited hippocampus and altered complex behavioral outcomes. Altered replay in calcineurin KO mice connects a schizophrenia-relevant developmental manipulation with dysfunctional adult hippocampal circuits and loss of a critical Gefitinib in vitro physiological process for learning. Thus, the loss of awake replay in calcineurin KO mice provides a glimpse into what could be fundamental

mechanisms perhaps relevant to cognitive deficits in schizophrenia and related disorders. The neurophysiological bases of cognitive deficits in schizophrenia and other disorders with altered cognition are not well known, and more rational use of animal models such as in Suh et al. (2013) is needed to advance schizophrenia research. Progress in this field may be limited by difficulties in reproducing critical aspects of these disorders in rodents and to unrealistic expectations about what animal models can deliver. The field has been

preoccupied, if not obsessed, with determining whether animal models are “valid,” and a large number of studies were aimed at establishing validity in different models. While validity criteria are useful for animal models of disorders with known etiology and/or pathophysiology, they have hampered research in psychiatry. We cannot expect to reproduce a disease as complex and uniquely human as schizophrenia in a rodent, and therefore all quest for validity is fraught. very However, we can utilize manipulations in rodents to test hypotheses related to possible etiological factors and/or pathophysiological scenarios; animal models are most useful when, instead of making any claims of disease reproduction, they are used as tools to probe specific hypotheses, such as behavioral or physiological consequences of genetic manipulations related to risk genes, the neurobiological impact of environmental factors contributing to risk for the disorder or testing consequences of altered developmental trajectories in brain circuits or cell types associated with schizophrenia (O’Donnell, 2013). Suh et al.

As the firing probability of the neuron is modified by an antidromic spike in a biphasic manner (i.e., inhibition-excitation), the firing rate and rhythm of the neuron would be disrupted. We showed that each antidromically activated CxFn

was influenced by a random but unique train of antidromic spikes that together would serve as a powerful means to desynchronize their coherent firing. Breaking of phase relationship among these CxFn could be a key to this process. Although Wilson et al. (2011) proposes DNA Damage inhibitor that a regular stimulus pattern of DBS causes the desynchronization, a randomly generated stimulus could also achieve the same effect. The idea that the local circuit BIBW2992 chemical structure can be affected by the antidromic spikes is supported by early studies that a late response was present in cortical cells that were not antidromically activated (Phillips, 1959; Porter and Sanderson, 1964; Stefanis

and Jasper, 1964). There is also recent evidence from human studies that STN-DBS has a direct effect on intracortical neurons, modifying the balance between excitation and inhibition (Fraix et al., 2008). In fact, our data also show that antidromic activation of the CxFn affected the firing of the interneurons (data not shown). While our results would lend support to the proposition that the cortex could be a therapeutic target in PD, epidural or subdural stimulation of cortex in human beings has been a subject of controversy. While some studies demonstrated promising results for treating PD patients (Benvenuti et al., 2006; Drouot et al., 2004), others were less supportive (Kuriakose et al., 2010; Strafella et al., 2007). Similarly, the results of transcranial magnetic stimulation were mixed (Benninger et al., 2011; Eggers et al., 2010; Khedr et al., 2006). It is likely Unoprostone that the efficacy of cortical stimulation

is dependent on the precise changes imposed on the activity of the cortical neurons, which in turn depends on the means, locations, and parameters of stimulation. It should be pointed out that the observed decrease in reliability of antidromic stimulation at high frequency is a nonclassical observation, in contrast to the three well-accepted criteria of antidromic spikes: fixed latency, collision, and frequency following (Lemon, 1984). A few factors could contribute to this phenomenon. First, the success of antidromic invasion to the neuronal soma in well-myelinated fibers is dependent on the membrane voltage of the soma, as observed by Chomiak and Hu (2007). They found that there was an overall sharp decrease in frequency following from −40mV to −60mV within the frequency range of 30–100 Hz. In the in vivo condition, it is likely that the membrane potential of the neurons is more hyperpolarized than −40mV, and therefore, one would not expect perfect fidelity in antidromic activation.