In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.

Land application of recycled manure produced from biosolids and reclaimed wastewater can transfer pharmaceutical chemicals to terrestrial environments, giving rise to potential accumulation of these residues in edible plants. In this study, the potential for plant uptake of 13 pharmaceutical chemicals, and the relation between the accumulation features within the plant and the physicochemical properties were examined by exposing pea and cucumber to an aqueous solution containing pharmaceutical chemicals. Ten of 13 compounds tested were detected in plant leaves and stems. Comparison of the plant uptake characteristics and the octanol-water partition coefficient of pharmaceutical chemicals showed that compounds with an intermediate polarity such as carbamazepine and crotamiton could be easily transported to plant shoots. Moreover, these results suggest the possibility of highly hydrophilic pharmaceutical chemicals such as trimethoprim and sulfonamides to be accumulated in plant roots owing to their low permeability in root cell membranes.

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective across anxiety-like and depression-like measures. Disruption of Drd1 activity also blocked the rapid antidepressant effects of ketamine. Finally, we demonstrate that stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant effects of somatic stimulation. These findings aid in understanding the cellular target neurons in the mPFC and the downstream circuitry involved in rapid antidepressant responses.

A fish plasma model (FPM) has been proposed as a screening technique to prioritize potential hazardous pharmaceuticals to wild fish. However, this approach does not account for inter- or intraspecies variability of pharmacokinetic and pharmacodynamic parameters. The present study elucidated the uptake potency (from ambient water), tissue distribution, and biological risk of 20 pharmaceutical and personal care product (PPCP) residues in wild cyprinoid fish inhabiting treated-wastewater-impacted streams. In order to clarify the uncertainty of the FPM for PPCPs, we compared the plasma bioaccumulation factor in the field (BAFplasma = measured fish plasma/ambient water concentration ratio) with the predicted plasma bioconcentration factor (BCFplasma = fish plasma predicted by use of theoretical partition coefficients/ambient water concentration ratio) in the actual environment. As a result, the measured maximum BAFplasma of inflammatory agents was up to 17 times higher than theoretical BCFplasma values, leading to possible underestimation of toxicological risk on wild fish. When the tissue-blood partition coefficients (tissue/blood concentration ratios) of PPCPs were estimated, higher transportability into tissues, especially the brain, was found for psychotropic agents, but brain/plasma ratios widely varied among individual fish (up to 28-fold). In the present study, we provide a valuable data set on the intraspecies variability of PPCP pharmacokinetics, and our results emphasize the importance of determining PPCP concentrations in possible target organs as well as in the blood to assess the risk of PPCPs on wild fish.

Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice

Efforts to develop efficacious antidepressant agents with novel mechanisms have largely unsuccessful since the 1950’s until the discovery of ketamine, an NMDA receptor antagonist that produces rapid and sustained antidepressant actions even in treatment resistant patients. This finding has ushered a new era for the development of novel rapid acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here we review the current state of rapid acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and increased synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.

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In the present study, we analyze and characterize the levels of PCBs and OH-PCBs in serum and breast adipose tissue, and measure TH (total 3,5,5'-triiodothyronine (tT3) and total l-thyroxine (tT4)) levels in serum of Japanese women diagnosed with breast cancer (n = 51) to know how PCBs affect thyroid hormone homeostasis. Concentrations of Sigma(90)OH-PCBs in serum and adipose tissues were 630 pg g(-1) serum wet wt. and 140 pg/ g(-1) lipid wt., respectively, and the levels of OH-PCBs in adipose tissues were 4-5 times lower than in serum. The tT3 and tT4 concentrations in serum (n = 20) were 1.3 ng g(-1) serum wet wt. and 62 ng g(-1) serum wet wt., respectively. Among all the OH-PCBs, 4'-OH-CB101/120, 4-OH-CB107/4'-OH-CB108, 3'-OH-CB138, 4-OH-CB146, 3-OH-CB153, 4'-OH-CB172, and 4-OH-CB187 were the dominant isomers in serum. No significant correlation between the concentrations of the TH and OH-PCBs in serum was observed (p > 0.05). The results indicated that the relationship between the OH-PCB levels and the thyroid hormone markers was rare. From analysis of two kinds of human biological samples, it was estimated that OH-PCBs have little effect on thyroid hormone homeostasis.