Nomura, T. | bioRxiv Science

bioRxiv2018

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

GABAA receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether distinct GABAA receptor subtypes contribute to seizure activity, and whether targeting receptor subtypes will have disproportionate benefit over adverse effects. Here we demonstrate that the 2 / 3 selective positive allosteric modulator (PAM) AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons. The effect of AZD7325 on synaptic responses was more prominent in mice on the 129S6/SvEvTac background strain that has been demonstrated to be seizure resistant in the model of Dravet syndrome (Scn1a+/-) and in which the 2 GABAA receptor subunits are higher relative to in the C57BL/6J strain. Consistent with this, treatment of mice with AZD7325 is associated with a higher temperature threshold for hyperthermia-induced seizures in Scn1a+/- mice without apparent sedative effects. Our results in a model system indicate that selective targeting 2 is a potential therapeutic option for Dravet syndrome.

neuroscience↗

bioRxiv2017

Which are major players, canonical or non-canonical strigolactones?

Strigolactones (SLs) can be classified into two structurally distinct groups: canonical and non-canonical SLs. Canonical SLs contain the ABCD ring system, and non-canonical SLs lack the A, B, or C ring but have the enol ether-D ring moiety which is essential for biological activities. The simplest non-canonical SL is the SL biosynthetic intermediate carlactone (CL). In plants, CL and its oxidized metabolites such as carlactonoic acid and methyl carlactonoate, are present in root and shoot tissues. In some plant species including black oat (Avena strigosa), sunflower (Helianthus annuus), and maize (Zea mays), non-canonical SLs are major germination stimulants in the root exudates. Various plant species such as tomato (Solanum lycopersicum) release carlactonoic acid, and poplar (Populus spp.) was found to exude methyl carlactonoate into the rhizosphere. These results suggest that both canonical and non-canonical SLs are active as host recognition signals in the rhizosphere. In contrast, limited distribution of canonical SLs in the plant kingdom and structure- and stereo-specific transportation of canonical SLs from roots to shoots suggest that plant hormones inhibiting shoot branching are not canonical SLs but are rather non-canonical SLs.\n\nSupplemental files: Synthesis of 7-hydroxy-5-deoxystrigol stereoisomers, spectroscopic data of synthetic compounds and the natural stimulant in dokudami root exudates.\n\nScheme S1. Synthesis of racemic mixture of 7- and 7{beta}-hydroxy-5-deoxystrigol.\n\nFig. S1. 1H NMR spectrum of natural stimulant in dokudami root exudates.\n\nFig. S2. LC-MS/MS chromatograms of synthetic standards and natural stimulant.\n\nFig. S3. LC-MS/MS chromatograms of synthetic 7{beta}-hydroxy-5-deoxystrigol and natural stimulant.\n\nFig. S4. LC-MS/MS chromatograms of synthetic 7{beta}-hydroxy-5-deoxystrigol and natural stimulant.\n\nHighlightThe chemistry of canonical and non-canonical strigolactones and their distribution in the plant kingdom are summarized in relation to their biological activities in the rhizosphere and in plants.

plant biology↗