γ-Hydroxybutyric Acid (GHB) is not an agonist of extrasynaptic GABAA receptors

γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents

State-dependent firing determines intrinsic dendritic Ca2+ signaling in thalamocortical neurons

Activity-dependent dendritic Ca2+ signals play a critical role in multiple forms of nonlinear cellular output and plasticity. In thalamocortical neurons, despite the well established spatial separation of sensory and cortical inputs onto proximal and distal dendrites, respectively, little is known about the spatiotemporal dynamics of intrinsic dendritic Ca2+ signaling during the different state-dependent firing patterns that are characteristic of these neurons. Here we demonstrate that T-type Ca2+ channels are expressed throughout the entire dendritic tree of rat thalamocortical neurons and that they mediate regenerative propagation of low threshold spikes, typical of, but not exclusive to, sleep states, resulting in global dendritic Ca2+ influx. In contrast, actively backpropagating action potentials, typical of wakefulness, result in smaller Ca2+ influxes that can temporally summate to produce dendritic Ca2+ accumulations that are linearly related to firing frequency but spatially confined to proximal dendritic regions. Furthermore, dendritic Ca2+ transients evoked by both action potentials and low-threshold spikes are shaped by Ca2+ uptake by sarcoplasmic/endoplasmic reticulum Ca2+ ATPases but do not rely on Ca2+-induced Ca2+ release. Our data demonstrate that thalamocortical neurons are endowed with intrinsic dendritic Ca2+ signaling properties that are spatially and temporally modified in a behavioral state-dependent manner and suggest that backpropagating action potentials faithfully inform proximal sensory but not distal corticothalamic synapses of neuronal output, whereas corticothalamic synapses only “detect” Ca2+ signals associated with low-threshold spikes

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Rhythmic dendritic Ca2+ oscillations in thalamocortical neurons during slow non-REM sleep-related activity in vitro

The distribution of T-type Ca2+ channels along the entire somatodendritic axis of sensory thalamocortical (TC) neurons permits regenerative propagation of low threshold spikes (LTS) accompanied by global dendritic Ca2+ influx. Furthermore, T-type Ca2+ channels play an integral role in low frequency oscillatory activity (<1–4 Hz) that is a defining feature of TC neurons. Nonetheless, the dynamics of T-type Ca2+ channel-dependent dendritic Ca2+ signalling during slow sleep-associated oscillations remains unknown. Here we demonstrate using patch clamp recording and two-photon Ca2+ imaging of dendrites from cat TC neurons undergoing spontaneous slow oscillatory activity that somatically recorded δ (1–4 Hz) and slow (<1 Hz) oscillations are associated with rhythmic and sustained global oscillations in dendritic Ca2+. In addition, our data reveal the presence of LTS-dependent Ca2+ transients (Δ[Ca2+]) in dendritic spine-like structures on proximal TC neuron dendrites during slow (<1 Hz) oscillations whose amplitudes are similar to those observed in the dendritic shaft. We find that the amplitude of oscillation associated Δ[Ca2+] do not vary significantly with distance from the soma whereas the decay time constant (τdecay) of Δ[Ca2+] decreases significantly in more distal dendrites. Furthermore, τdecay of dendritic Δ[Ca2+] increases significantly as oscillation frequency decreases from δ to slow frequencies where pronounced depolarised UP states are observed. Such rhythmic dendritic Ca2+ entry in TC neurons during sleep-related firing patterns could be an important factor in maintaining the oscillatory activity and associated biochemical signalling processes, such as synaptic downscaling, that occur in non-REM sleep

Dopaminergic modulation of tonic but not phasic GABAA-receptor-mediated current in the ventrobasal thalamus of Wistar and GAERS rats

Activation of GABAA receptors by GABA causes phasic and tonic conductances in different brain areas. In the ventrobasal (VB) thalamus, tonic inhibition originates from GABA acting on extrasynaptic receptors. Here we show that dopamine (DA), the D2-like agonist quinpirole and the selective D4R agonist PD-168,077 decrease the magnitude of the tonic GABAA current while D1-like agonist SKF39383 lacks any significant effects in VB neurons of Wistar rats. On the other hand, DA and D1/D2 receptor activation does not alter phasic GABAA conductance. As we previously reported that an increased tonic GABAA current in VB neurons is critical for absence seizure generation, we also investigated whether D2–D4 receptor activation is capable of normalizing this aberrant conductance in genetic absence epilepsy rats from Strasbourg (GAERS). Quinpirole and PD-168,077 selectively reduces tonic GABAA current as in normal rats. Therefore, it is conceivable that some DA anti-absence effects occur via modulation of tonic GABAA current in the VB

The thalamus as a low pass filter: filtering at the cellular level does not equate with filtering at the network level.

In the mammalian central nervous system, most sensory information passes through primary sensory thalamic nuclei, however the consequence of this remains unclear. Various propositions exist, likening the thalamus to a gate, or a high pass filter. Here, using a simple leaky integrate and fire model based on physiological parameters, we show that the thalamus behaves akin to a low pass filter. Specifically, as individual cells in the thalamus rely on consistent drive to spike, stimuli that is rapidly and continuously changing over time such that it activates sensory cells with different receptive fields are unable to drive thalamic spiking. This means that thalamic encoding is robust to sensory noise, however it induces a lag in sensory representation. Thus the thalamus stabilises encoding of sensory information, at the cost of response rate