Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine’s antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.

Seed vigor is an important characteristic of seed quality, and rice cultivars with strong seed vigor are desirable in direct-sowing rice production for optimum stand establishment. In the present study, the quantitative trait loci (QTLs) of three traits for rice seed vigor during the germination stage, including germination rate, final germination percentage, and germination index, were investigated using one recombinant inbred line (RIL) population derived from a cross between japonica Daguandao and indica IR28, and using the multiple interval mapping (MIM) approach. The results show that indica rice presented stronger seed vigor during the germination stage than japonica rice. A total of ten QTLs, and at least five novel alleles, were detected to control rice seed vigor, and the amount of variation (R(2)) explained by an individual QTL ranged from 7.5% to 68.5%, with three major QTLs with R(2)>20%. Most of the QTLs detected here are likely to coincide with QTLs for seed weight, seed size, or seed dormancy, suggesting that the rice seed vigor might be correlated with seed weight, seed size, and seed dormancy. At least five QTLs are novel alleles with no previous reports of seed vigor genes in rice, and those major or minor QTLs could be used to significantly improve the seed vigor by marker-assisted selection (MAS) in rice.

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Infectious keratitis remains the most common indication for PKP in north China. Moreover, there is an increasing trend in the percentage of PKP for keratoconus and bullous keratopathy.