Our reconstitution experiments also allowed us to begin to address the requirements for the delivery and DAPT nmr maintenance of the GLR-1 signaling complex. One possibility is that SOL-1 might have an obligate chaperone role for some critical component of the complex, much like that suggested for a subset of the vertebrate TARPs (Milstein

and Nicoll, 2008). In this scenario, the delivery or stability of components of the complex would be compromised in the absence of SOL-1. Alternatively, the components might reside stably at the membrane. To help distinguish between these possibilities, we expressed GFP-tagged secreted s-SOL-1 (GFP::s-SOL-1) in muscle cells of transgenic sol-1 mutants using selleck products the myo-3 muscle-specific promoter. If GLR-1, STGs, SOL-2 and any other necessary components of the complex are stably delivered to the postsynaptic membrane in the absence of SOL-1, then one might predict that s-SOL-1 delivered in trans from muscle cells in transgenic sol-1 mutants would be sufficient to restore a functional signaling complex in AVA. We first examined whether GFP::s-SOL-1 delivered in trans from muscle cells was colocalized with GLR-1 in the processes of the AVA interneurons. We coexpressed muscle-secreted

GFP::s-SOL-1 and AVA-specific GLR-1::mCherry in transgenic mutants. We found that GFP::s-SOL-1 and GLR-1::mCherry colocalized at puncta along the length of the AVA processes in sol-1 mutants ( Figure 4A), but not in sol-1; sol-2 double mutants ( Figure 4B). We also observed GFP puncta along the AVA processes

when muscle secreted GFP::s-SOL-1 was expressed in the absence of the GLR-1::mCherry transgene ( Figure S5A). This result indicates that localization of s-SOL-1 to the ventral cord does not require overexpression of GLR-1 or other components of the signaling complex. This localization was also dependent on SOL-2, and thus GFP::s-SOL-1 was not observed along the ventral cord in sol-1; sol-2 double mutants ( Figure S5B). We also found that the hyperreversal movement of sol-1; lurcher mutants was rescued by muscle secreted GFP::s-SOL-1 and that the rescue was dependent on SOL-2 ( Figure 4C). Our behavioral analysis suggested that s-SOL-1 provided in trans Thymidine kinase restored GLR-1-mediated signaling in the command interneurons. To more directly examine signaling, we measured glutamate-gated currents in AVA interneurons of sol-1 mutants, sol-1; sol-2 double mutants, and transgenic mutants that expressed s-SOL-1 in muscle cells. In either sol-1 or sol-1; sol-2 double mutants we could not detect rapidly activating glutamate-gated currents. However, we found partial recovery of the current in transgenic sol-1 mutants that expressed s-SOL-1 (77.25 ± 28.31 pA, n = 4), but not in transgenic sol-1; sol-2 mutants (n = 3), indicating that the function of s-SOL-1 was dependent on SOL-2 in AVA interneurons ( Figure 4D).

0 ml of C. elegans axenic culture 5–7-day old were transferred to a 50-ml tube and the volume

was completed with XAV939 sterile distilled water. All stages of the life cycle were present and the tube was placed in a rack for 3 min to allow settling of the largest nematodes. The surface water containing smaller floating nematodes was then removed to reduce the volume to approximately 0.5 ml. Nematodes were separated according to their size using two sieves. Sieves were created by inserting nylon filter cloth between 2 pieces of PVC pipe of 2.1 and 1.9 cm diameter. First, we used a sterile 38 μm sieve to retain the largest nematodes and allow smaller nematodes to migrate through the sieve. This procedure retained young adults, adults, and large dead nematodes, which were non-motile and straightened ( Fig. 1). Approximately 10 ml

of distilled water was used to facilitate the migration. Nematodes retained in the 38-μm sieve were transferred with 50 ml sterile water onto a larger mesh 53-μm sieve. In this procedure all active nematodes (adults and young adults) passed through the mesh and all dead or inactive EGFR inhibitor drugs nematodes were retained by the 53-μm sieve (Fig. 2). The selection process was performed twice with each sieve, resulting in a suspension in which approximately 100% of the adult nematodes were alive and active. The final solution had a concentration of approximately 50 nematodes/20 μl. Tests were performed using a balanced salt solution (M-9) as the diluent for solvents and M-9 was also used as the medium to prepare a nematode stock with 50 nematodes/20 μl. M-9 solution was composed of 1.5 g KH2PO4, 3 g Na2HPO4, 2.5 g NaCl, 0.5 ml 1 M MgSO4, and sterile distilled water to bring the volume to 500 ml (Brenner, 1974). Tests were performed in 24-well plates containing a total volume of 250 μl/well, with 6 replicates per treatment. The 24-well plates were covered with transparent plastic, and incubated at 24 °C for 24 h. The M-9 medium produced better nematode

survival than using distilled water, perhaps because the medium better preserved the nematode’s osmotic balance. After incubation at 24 °C for 24 h, plates were read using an inverted microscope and all nematodes counted and determined as MTMR9 motile or non-motile. They were considered motile when they exhibited any movement, and as non-motile when there were no tail, head, or pharyngeal movements during 5 s of observation (Skantar et al., 2005). It is important to differentiate motility in adult nematodes from movement caused by larvae hatched from eggs inside the body of dead C. elegans. The negative control group consistently showed 95–100% motile nematodes and the positive control (levamisole) 0% motile nematodes 24 h after incubation. To facilitate counting of 50 nematodes/well, horizontal lines were drawn at the bottom of the plates at 0.1 mm distance intervals. Our work indicates that the method using liquid C. elegans cultures is a fast and reliable way to propagate and synchronize C. elegans.

(2011) find that low external Ca2+ increases the open-probability CP 673451 of the OHC MT channel to near 0.5, thereby enhancing MT currents even with no stimulus. As a result, threshold sounds are expected to produce transducer currents at the most sensitive point of displacement-transducer current curve (Figure 1) and OHCs would also have higher MT resting currents. Consequently resting potentials would be more positive than previously thought,

perhaps close to −40 mV. Sharp microelectrode recordings in the early 1980s suggested that OHCs had a resting potential around −60 to −70 mV. With the hindsight of 20 years of OHC biophysics it seems possible that the methods could have biased the resting potentials to more negative levels, possibly by mechanically bending the hair cell stereocilia slightly during recording. And third, the depolarized OHCs have GDC-0973 supplier a high resting K+ conductance.

The OHC basolateral K+ conductance is largely determined by KCNQ4 (Kubisch et al., 1999) albeit with a channel modifier that strongly shifts activation in the negative direction. However, in vivo OHC resting potentials near −40 mV would imply that the KCNQ4 channel is nearly fully activated. The effect would be to produce a high resting conductance, a short cell membrane time constant and therefore a large enough receptor potential to drive prestin, at least for cochlear positions up to about 10 kHz as explored in the paper. What happens at still higher frequencies? Some mammalian cochleas, including those of many rodents, are functionally Mannose-binding protein-associated serine protease responsive to sounds

2–3 octaves higher (indeed a mouse uses only the most apical 20% of its cochlea for the range considered normal by humans). Is it still possible that prestin is not the mechanism employed at those highest frequencies? The prediction of the Johnson et al. (2011) paper is that OHC transduction and basolateral currents should continue to increase together toward the cochlear base. The cells from this region of the cochlea have resisted detailed study, except by extrapolation from measurements at lower frequencies. Remarkably, the density of K+ channels in OHCs increases exponentially along the cochlea toward the basal (high frequency) end, making it increasingly difficult to record from these cells. The cells at the cochlear base are also smaller and exceptionally fragile; even the stereocilia are shorter (less than 1 μm tall) rendering them difficult to stimulate in vitro. Worse, conventional patch clamp recording amplifiers have bandwidths limited to around 10 kHz. All of these factors conspire to make obtaining reliable data from high frequency cells that much harder and modeling the anticipated behavior becomes increasingly a part of the experiment. It may be that prestin is driven not only by the intracellular potentials, but also by contributions from the extracellular potential fields surrounding the OHCs ( Mistrík et al., 2009 and Dallos and Evans, 1995).

The peak release rates were strongly reduced in RIM1/2 cDKO synapses (Figure 5D) and the width of the transmitter release at half-maximal amplitudes was longer in RIM1/2 cDKO synapses (5.1 ± 1.8 ms, n = 6) than in control (2.3 ± 1.1 ms, n = 5; p < 0.05).

The integrated release rate traces were fitted with a series of single- and double-exponential function with or without line component to determine the best fit function (see Experimental Procedures). In both genotypes, cumulative release was best fitted by functions that contained at least two exponential components (Figure 5C, blue fit lines), indicating a fast and a slow release component (Sakaba and Neher, 2001, Wadel et al., 2007 and Wölfel et al., 2007). In RIM1/2 cDKO synapses, the fast release time mTOR inhibitor constant was significantly slower (5.2 ± 1.7 ms, n = 6) than in control synapses (1.8 ± 0.8 ms, n = 5; Figure 5E; p = 0.002), but it was significantly faster than the slow release time constant in control synapses, find more which was 23 ± 3.7 ms (n = 5; Figure 5F; p < 0.001). Similarly, when cumulative release

traces were arbitrarily fitted with monoexponential functions, the resulting time constant in RIM1/2 cDKO synapses (9.3 ± 1.1 ms; n = 6) was still significantly faster than the slow release time constant in wild-type cells (p < 0.001). Both of these comparisons show that the FRP is not simply missing completely but rather that release from the remaining FRP is slowed in the RIM1/2 cDKO synapses. Figures 5E and 5F show further parameters extracted from the kinetic analysis of transmitter release for each genotype. PDK4 Overall, the analysis shows a strongly reduced number of readily releasable vesicles in both the FRP and the SRP, as well as a significant, ∼2.5-fold slowing of the fast release component. The kinetics of transmitter release in response to Ca2+ influx depends on the intrinsic speed of release, as well as on the “local” [Ca2+]i that builds up close to the readily releasable vesicles, which, in turn, is a function of the distance between Ca2+ channels and vesicles (Neher,

1998 and Wadel et al., 2007). The Ca2+ uncaging experiments showed that the intrinsic Ca2+ sensitivity is reduced in the absence of RIM1/2 (Figure 4). To ask whether the spatial coupling between Ca2+ channels and vesicles was impaired as well, we back-calculated the local [Ca2+]i that was necessary to reproduce the kinetics of the fast release component in response to depolarizations (Figures 5B and 5C, gray traces; Schneggenburger and Neher, 2000). This was done by using the specific sets of kinetic parameters that describe the intracellular Ca2+ sensitivities of transmitter release of RIM1/2 cDKO and control synapses (Figure 4). In the examples of Figure 5C, a step-like local [Ca2+]i signal of 7.

Together, these studies provide us with an excellent—though incomplete—neural framework to understand how converging sensory inputs are interpreted to induce a selection between alternative behavioral outputs. The available data point to the P1 cluster as the critical central neurons that trigger singing (and other aspects of the courtship routine), but how might these neurons weigh up positive and negative sensory influences

on the decision to initiate courtship? A hint is offered by finer-scale thermal activation experiments of von Philipsborn et al. (2011), who found that Venetoclax at least ten out of 20 individual P1 neurons must express TrpA1 to induce singing. While it is unknown whether these cells are functionally homogeneous, it is intriguing to speculate that attainment of this threshold number of activated P1 neurons in wild-type flies may be what tips INCB018424 purchase the balance in their mind in favor of courting. Future high-resolution anatomical mapping and physiological characterization of excitatory and inhibitory synaptic inputs to these neurons from different sensory systems, as well as their precise output pathways may reveal the cellular mechanisms by which neural circuits make decisions. “
“Given the increasing prevalence of obesity and the devastating comorbidities associated with obesity, identifying effective antiobesity strategies is

more imperative than ever. Although the underlying causes of the obesity epidemic are multifactorial, exposure to high-caloric diet (Western diet) is thought to be one of the major reasons. In order to mimic human obesity in animal models, a widely accepted strategy involves inducing obesity in rodent models with high-fat diet (HFD) feeding. The HFD feeding can induce obesity and metabolic disorders in rodents that resemble the human metabolic syndrome (Buettner et al., 2007). Thus, important antiobesity drug targets can be identified with HFD-induced obesity models. Research efforts in the last decades have established that the hypothalamus plays a central role in body weight regulation.

The hypothalamus contains diverse groups of body weight-regulating neurons that release distinct neurotransmitters, the most studied of which are neuropeptides (Elmquist others et al., 2005). Recent evidence suggests that the oxytocin-releasing neurons, located in the paraventricular hypothalamus (PVH) and the supraoptic nucleus, are implicated in body weight regulation in addition to their well-established role in social cognition (Donaldson and Young, 2008). Reduced oxytocin expression has been associated with mouse models of obesity (Kublaoui et al., 2008); pharmacological studies demonstrate that oxytocin inhibits feeding involving a projection from the PVH to the hindbrain, where meal size is regulated (Blevins et al.

In humans, a highly homologous gene, SMN2, which lies centromeric to SMN1 on chromosome www.selleckchem.com/products/Bosutinib.html 5q, partially but poorly compensates for reduced SMN levels. While five nucleotides, none of which lead to an amino acid change, differentiate SMN2 from SMN1, SMN2 mRNA, through alternative splicing, results predominantly in transcripts lacking exon 7, thereby leading to a truncated, unstable

protein (Lorson et al., 2010). Only 10% of the transcripts are translated into functional full-length SMN protein. As a result, SMN2 normally contributes little to the overall levels of full-length SMN protein. However, copy numbers of the SMN2 gene in the human genome are variable, ranging from 0 to 4 copies in the genome. Higher SMN2 copy numbers result in increased full-length protein levels, which correlate with milder phenotypes in patients (Mailman et al., 2002). As such, current targets for therapy have focused on drugs that either promote overall SMN2 expression or promote exon 7 inclusion (Sendtner, 2010). While transgenic mouse models exist, mice lack SMN2 and homozygous knockout of SMN1 leads to embryonic lethality, which has necessitated generating PD0332991 transgenic mice that harbor human SMN2 (Hsieh-Li et al., 2000 and Monani et al., 2000). To create a patient-specific iPS cell model of SMA, skin fibroblasts were obtained from a child with SMA type 1. The subject was 3 years old at the time of sample collection

and had two copies of SMN2. Fibroblasts from his unaffected mother were also reprogrammed to iPS cells by lentiviral transduction of OCT4, SOX2, NANOG, and LIN28 ( Ebert et al., 2009). One iPS clone from the SMA child

(iPS-SMA) and the unaffected mother (WT-iPS) was subsequently used in their studies. As expected, SMA fibroblasts and iPS cells lacked SMN1 expression, expressed the alternatively spliced delta exon 7 mRNA, and demonstrated reduced levels of full-length those SMN contributed by SMN2 expression. Following directed differentiation of iPS cells to spinal motor neurons, no significant differences in motor neuron numbers were seen after a total of 4 weeks of in vitro differentiation. At 6 weeks, the total numbers of neurons, based on the overall number of cells positive for neuronal marker TUJ1, were equivalent between WT and SMA (15.78% in WT and 15.55% in SMA). However, when cultures were specifically evaluated for motor neurons based on coexpression of TUJ1 and ChAT, motor neuron numbers were reduced from the SMA cultures (4.3% in SMA versus 24.2% in WT). In addition, SMA-iPS motor neurons were smaller in soma size and synapse formation appeared to be compromised ( Ebert et al., 2009). To demonstrate that SMN production could pharmacologically be altered in this disease line, two drugs known to increase SMN production were tested. SMN can be localized to discrete, punctuate structures called “gems” (Liu and Dreyfuss, 1996).

We would like to thank Nick Yeung and Kia Nobre for providing access to their EEG equipment, Nick Myers for assistance with EEG acquisition, and Tim Behrens, Etienne Koechlin, Benjamin Morillon, and Mark Stokes for useful suggestions and comments. V.W. is supported by a postdoctoral research grant from the Fyssen Foundation. “
“Dopamine (DA) and acetylcholine (ACh) have long been

thought to be the Hatfields and McCoys of the striatum—constantly feuding for control. Based upon articles by Threlfell et al. (2012) in this issue of Neuron and Cachope et al. (2012) in Cell Reports, it seems that we’ve misjudged this grudge match. We’ve known for a long time that DA and ACh are important to the striatum and to selleckchem the functions of the basal ganglia in health and disease. Striatal levels of the proteins associated with these two neuromodulators (e.g., synthetic enzymes, receptors) are among the highest of any region in the brain. DA in the striatum is released from the widespread axonal arbors of neurons whose cell bodies reside in the midbrain substantia nigra pars compacta, whereas the ACh comes from the giant striatal cholinergic interneurons (ChIs). Both neuromodulators are critically important for basal-ganglia-based disorders, and both have been strongly implicated in the striatal regulation

of ongoing behaviors and learning. The notion that there is a feud between DA and ACh stretches back decades to clinical observations suggesting that they reciprocally control motor behaviors. In Parkinson’s disease, for example, striatal DA levels plummet and ACh Selleckchem C646 levels appear to rise. Anticholinergic drugs, which nominally leveled the playing field, were used as one of the most effective treatments for the motor symptoms of PD early on (before the discovery of levodopa). Based on work by not Barbeau, the metaphor of a child’s

see-saw was used to capture the apparent antagonism, implying that when the effects of DA fell, those of ACh went up. But the evidence for the feud has been decidedly one sided. It is very clear from a long parade of biochemical and physiological studies that DA suppresses ACh release. This inhibition is accomplished through G protein-coupled receptors for DA that reduce the spontaneous spiking of ChIs and the terminal release of ACh (Gerfen and Surmeier, 2010). The effects of ACh on DA release have been much more difficult to see clearly. There are acetylcholine receptors on the terminals of dopaminergic axons. Studies mostly suggest that ACh diminishes DA release, creating a symmetry with DA modulation of ACh release, but there is not a clear consensus on this point (Rice et al., 2011). In situations like this, there is often a technical hurdle that has been difficult to overcome. So it is for Ach-DA interactions.

, 2010). These data suggest a basic neurogenic theme in the VZ: NSCs in the VZ of the developing rodent and primate telencephalon divide to generate neurons as well as additional classes of dividing progenitors (such as Tbr2+ INPs, SNPs, and OSVZ cells), which amplify the total neuron output. In primate VZ, this mechanism appears more robust and has likely been modified to include additional RGC and progenitor cell types that act in concert to produce the vastly larger pool of neurons during development. Beyond this, recent global transcriptome analysis of human

brain development Selleck Epigenetic inhibitor suggests that there has been rapid human-specific evolution of cis-regulatory elements leading to differentially regulated regional expression of genes in different cortical areas ( Johnson et al., 2009). This may partially underlie some of the major species-specific differences. Taken together, these studies indicate

that NSC biology is extremely complex and that allocation into segregated stem and progenitor cell populations is a key element of proper brain development. These and GDC-0068 in vivo other studies in rodents carefully set the stage for and demarcate the limits of endogenous stem cell activity and potential. These boundaries are now being tested in the burgeoning field of adult stem cell manipulation and therapeutic intervention. During the early part of this century, tissue-specific stem cells continued to receive significant attention due to rapid methodological advances in viral labeling, mouse genetics, and development of culturing methods (Wagers and Weissman, 2004). As a result of
age studies, the boundaries that had seemingly existed for decades seemed to fall as reports of hematopoietic cells becoming brain cells, including neurons, appeared MycoClean Mycoplasma Removal Kit (Brazelton et al., 2000 and Mezey et al., 2000). Furthermore, neuronal addition to areas beyond the hippocampus and olfactory bulb were suggested (Gould et al., 1999 and Zhao et al., 2003). However, many

of these claims have failed to hold up to scrutiny, seemingly due to methodological reasons (Ackman et al., 2006, Alvarez-Dolado et al., 2003, Breunig et al., 2007, Castro et al., 2002 and Kornack and Rakic, 2001). However, it did become evident that NSCs could produce functional neurons in vitro and in some areas in vivo in rodents as well as in some other mammals. For example, areas of adult neurogenesis, such as the hippocampus and subventricular zone, allowed neurogenesis from transplanted NSCs (Gage et al., 1995), including hESC-derived NSCs (Muotri et al., 2005). Other regions, such as the substantia nigra, were recalcitrant to neurogenesis (Lie et al., 2002). Endogenous NSCs in the hippocampus and olfactory bulb in young adult mice did proceed through the differentiation profile characteristic of embryonic neurons (Carleton et al., 2003 and Song et al., 2002). These neurons integrated into existing circuits and produced action potentials (van Praag et al., 2002).

If the cortical circuit contributes to response variability, for example, through its recurrent

elements, then silencing the cortex should reduce that variability. To silence a small patch of the cortex around the recording electrode, we used local electrical click here stimulation (Chung and Ferster, 1998) and compared trial-to-trial variability before and during inactivation. Since electrical stimulation only affords a brief (∼100 ms) period during which the cortex is silenced, we measured variability and the effects of cortical silencing in the responses to briefly flashed gratings instead of drifting gratings. Before inactivating the cortex, we first examined whether orientation tuning of the Vm responses to flashed gratings was, in fact, contrast-invariant, as it is for drifting gratings. For the example cell in Figure 1, the width of orientation tuning was indeed similar across contrasts (Figure 1C), with only a slight narrowing at the lowest contrast (4%), as can

be seen in the normalized tuning curves of Figure 1D. Over the population, tuning width at high contrast (mean σ = 32°) was not significantly different than it was at low contrast (35°; paired t test, p = 0.20; n = 21). We next confirmed that the trial-to-trial variability in Vm responses increases with decreasing contrast for flashed gratings as it does for drifting gratings. This change in variability can be seen in Figure 1E Selumetinib nmr by comparing the trial-to-trial SD of the responses at high-contrast (gray and cyan shading) with the low-contrast SD (magenta shading). Detailed changes in the distribution of the response amplitudes in four additional cells are shown as kernel density estimates in Figure S2A (available online), where it can be seen that the Vm distributions evoked by low-contrast preferred stimuli were wider or more right-skewed than those evoked by high-contrast null stimuli. An indication of the contrast-dependent, but orientation-independent changes in PD184352 (CI-1040) variability can also be seen in the error

bars (SEM) of Figure 1C (compare circles). We quantified peak Vm variability for each stimulus condition as the SD of the Vm response in a 2.5 ms window centered on the peak of the mean Vm response. For the population of cells in Figure 1, the peak Vm SDs for high-contrast preferred stimuli, high-contrast null stimuli and low-contrast preferred stimuli were 3.66, 3.24, and 3.88 mV, similar to the values observed for drifting grating stimuli. Of the 35 cells studied, 26 showed higher Vm variability for low-contrast preferred stimuli (∼75%) than for high-contrast null stimuli. On average, peak Vm variability for low-contrast preferred stimuli was 22% greater than variability for high-contrast null stimuli (n = 35, p < 0.01, paired t test; Figure 1F).

In a subset of cells, we measured the SR95531-dependent increase of spontaneous APs (from 7.4 ± 0.6 to 12.66 ± 1.2 Hz, n = 7, see Häusser and Clark, 1997) that we adjusted with DC current (7.4 ± 0.5 pA) to match the observed rate in control conditions. Experiments were performed using Epacadostat research buy internal solutions with Alexa Fluor 488 or 568 hydrazide (100 μM; Life Technologies) or 0.2% biocytin. Slices were fixed in 4% paraformaldehyde for 1 hr and mounted with anti-fade reagent (ProLong Gold, Life Technologies), or

incubated with streptavidin-conjugated Alexa Fluor 647 prior to mounting. Digital images were acquired using a 20× (NA 0.85) oil-immersion objective on an Olympus FluoView 300 confocal microscope. Images were reconstructed in Neurolucida (MicroBrightField). Data was analyzed using AxoGraphX software. Changes

to basal spontaneous action potential rate were quantified as in Mittmann et al. (2005). Briefly, peristimulus Rapamycin chemical structure histograms (PSHs) were computed and integrated. A linear fit to the baseline of the integral was extrapolated over the entire sweep and subtracted from the integral to yield the cumulative spike probability plot. We averaged between 300–400 ms period after stimulation to measure the number of spikes evoked by the input. Data are displayed as means ± SEM, and significance was analyzed with two-tailed Student’s t tests (Microsoft Excel and GraphPad Prism). n values indicate number of cells. Spearman or Pearson correlations were used depending on the normality of the data. ANOVAs were followed by Bonferroni’s multiple comparison test unless noted. SR95531 (GABAAR antagonist, 5 μM), oxyclozanide NBQX (AMPAR antagonist, 10 μM), AP5 (NMDAR antagonist,

100 μM), and QX314 (Na+-channel blocker, 5 mM) were obtained from Abcam. DL-TBOA (50 μM) was purchased from Tocris Bioscience. All other chemicals and compounds were obtained from Sigma or Fisher Scientific. This work was supported by NIH NS064025 (L.O.-W.) and NS065920 (J.I.W.). We thank Kamran Khodakhah, Ming-Chi Tsai, Anastassios Tzingounis, and members of the Wadiche laboratories for discussions and reading the manuscript. “
“Allosteric modulation can profoundly regulate the function of ion channels and G protein-coupled receptors in either a positive or negative direction (Conigrave and Franks, 2003; Schwartz and Holst, 2007) and is of increasing interest for both physiology and pharmacology. Benzodiazepines (BZs) act as allosteric modulators on type-A receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA). BZs act as either positive allosteric modulators (PAMs) and prolong currents through GABAARs to increase the duration and strength of inhibitory signals, or as negative allosteric modulators (NAMs, or inverse agonists) (Sieghart, 1995).