During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

AbstractAs neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity

A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant

OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions

A study of CP violation in the decays B±→[K+K-π+π-]Dh± (h= K, π) and B±→[π+π-π+π-]Dh±

The first study of CP violation in the decay mode B±→[K+K-π+π-]Dh± , with h= K, π , is presented, exploiting a data sample of proton–proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of 9 \,fb - 1 . The analysis is performed in bins of phase space, which are optimised for sensitivity to local CP asymmetries. CP -violating observables that are sensitive to the angle γ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for B±→[K+K-π+π-]Dh± and B±→[π+π-π+π-]Dh± decays

First observation and branching fraction measurement of the Λb0→Ds−p\Lambda_b^0\to D_s^- p decay

The first observation of the $\Lambda_b^0\to D_s^- p$ decay is presented using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of ${\sqrt{s}=13 \,\textrm{TeV}}$, corresponding to a total integrated luminosity of $6\,\textrm{fb}^{-1}$. Using the $\Lambda_b^0\to\Lambda_c^+\pi^-$ decay as the normalisation mode, the branching fraction of the $\Lambda_b^0\to D_s^- p$ decay is measured to be ${\mathcal{B}(\Lambda_b^0\to D_s^- p)=(12.6 \pm 0.5 \pm 0.3 \pm 1.2 )\times 10^{-6}}$, where the first uncertainty is statistical, the second systematic and the third due to uncertainties in the branching fractions of the $\Lambda_b^0\to\Lambda_c^+\pi^-$, $D_s^- \to K^-K^+\pi^-$ and $\Lambda_c^+\to p K^- \pi^+$ decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-038.html (LHCb public pages

First observation of a doubly charged tetraquark and its neutral partner

A combined amplitude analysis is performed for the decays $B^0 \rightarrow \overline{D}^0 D^+_s\pi^-$ and $B^+\rightarrow D^- D^+_s\pi^+$, which are related by isospin symmetry. The analysis is based on data collected by the LHCb detector in proton-proton collisions at center-of-mass energies of 7, 8 and 13$\,\rm{TeV}$. The full data sample corresponds to an integrated luminosity of 9$\,\rm{fb^{-1}}$. Two new resonant states with masses of $2.908\pm0.011\pm0.020\,\rm{GeV}$ and widths of $0.136\pm0.023\pm0.011\,\rm{GeV}$ are observed, which decay to $D^+_s\pi^+$ and $D^+_s\pi^-$ respectively. The former state indicates the first observation of a doubly charged open-charm tetraquark state with minimal quark content $[c\bar{s}u\bar{d}]$, and the latter state is a neutral tetraquark composed of $[c\bar{s}\bar{u}d]$ quarks. Both states are found to have spin-parity $0^+$, and their resonant parameters are consistent with each other, which suggests that they belong to an isospin triplet.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-026.html (LHCb public pages

Study of charmonium decays to KS0KπK^0_S K \pi in the B→(KS0Kπ)KB \to (K^0_S K \pi) K channels

A study of the $B^+\to K^0_SK^+K^-\pi^+$ and $B^+\to K^0_SK^+K^+\pi^-$ decays is performed using proton-proton collisions at center-of-mass energies of 7, 8 and 13 TeV at the LHCb experiment. The $K^0_SK \pi$ invariant mass spectra from both decay modes reveal a rich content of charmonium resonances. New precise measurements of the $\eta_c$ and $\eta_c(2S)$ resonance parameters are performed and branching fraction measurements are obtained for $B^+$ decays to $\eta_c$, $J/\psi$, $\eta_c(2S)$ and $\chi_{c1}$ resonances. In particular, the first observation and branching fraction measurement of $B^+ \to \chi_{c0} K^0 \pi^+$ is reported as well as first measurements of the $B^+\to K^0K^+K^-\pi^+$ and $B^+\to K^0K^+K^+\pi^-$ branching fractions. Dalitz plot analyses of $\eta_c \to K^0_SK\pi$ and $\eta_c(2S) \to K^0_SK\pi$ decays are performed. A new measurement of the amplitude and phase of the $K \pi$ $S$-wave as functions of the $K \pi$ mass is performed, together with measurements of the $K^*_0(1430)$, $K^*_0(1950)$ and $a_0(1700)$ parameters. Finally, the branching fractions of $\chi_{c1}$ decays to $K^*$ resonances are also measured.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-051.html (LHCb public pages

First observation of the B+→Ds+Ds−K+B^+ \rightarrow D_s^+ D_s^- K^+ decay

The $B^+ \rightarrow D_s^+ D_s^- K^+$ decay is observed for the first time using proton-proton collision data collected by the LHCb detector at centre-of-mass energies of $7$, $8$ and $13\, \text{TeV}$, corresponding to an integrated luminosity of $9\,\text{fb}^{-1}$. Its branching fraction relative to that of the $B^{+} \rightarrow D^{+} D^{-} K^{+}$ decay is measured to be $$\frac{B\left(B^{+} \rightarrow D_s^{+} D_s^{-} K^{+}\right)}{B\left(B^{+} \rightarrow D^{+} D^{-} K^{+}\right)}=0.525 \pm 0.033 \pm 0.027 \pm 0.034,$$ where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the $D_s^{\pm} \rightarrow K^{\mp} K^{\pm} \pi^{\pm}$ and $D^{\pm} \rightarrow K^{\mp} \pi^{\pm} \pi^{\pm}$ decays. This measurement fills an experimental gap in the knowledge of the family of Cabibbo$-$favoured $\bar{b} \rightarrow \bar{c} c \bar{s}$ transitions and opens the path for unique studies of spectroscopy in future.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-019.html (LHCb public pages

Observation of the Bs0 ⁣→D∗+D∗−B^0_s\!\to D^{*+}D^{*-} decay

The first observation of the $B^0_s\!\to D^{*+}D^{*-}$ decay and the measurement of its branching ratio relative to the $B^0\!\to D^{*+}D^{*-}$ decay are presented. The data sample used corresponds to an integrated luminosity of 9$\,\text{fb}^{-1}$ of proton-proton collisions recorded by the LHCb experiment at centre-of-mass energies of 7, 8 and 13$\,\text{TeV}$ between 2011 and 2018. The decay is observed with a very high significance and the ratio of branching fractions is determined to be \begin{align*} \frac{\mathcal{B}(B^0_s\!\to D^{*+}D^{*-})}{\mathcal{B}(B^0\!\to D^{*+}D^{*-})} = 0.269 \pm 0.032 \pm 0.011 \pm 0.008\, , \end{align*} where the first uncertainty is statistical, the second systematic and the third due to the uncertainty of the fragmentation fraction ratio $f_s/f_d$. The $B^0_s\!\to D^{*+}D^{*-}$ branching fraction is calculated to be \begin{align*} \mathcal{B}(B^0_s\!\to D^{*+}D^{*-}) = (2.15 \pm 0.26 \pm 0.09 \pm 0.06 \pm 0.16)\times 10^{-4} \,, \end{align*} where the fourth uncertainty is due to the $B^0\!\to D^{*+}D^{*-}$ branching fraction.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-023.html (LHCb public pages