The rapid antidepressant response after ketamine administration in treatment resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rat. Moreover, blockade of mTOR signaling completely blocked ketamine-induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner.

This communication describes the use of polyelectrolyte multilayer as a preformed matrix in electrochemical deposition to adjust the morphology of gold clusters, and only the surface covered with dendritic gold clusters shows a super-hydrophobic property, with the contact angle above 150 degrees and the tilt angle less than 1.5 degrees , after the surface further chemisorbed with a self-assembled monolayer of n-dodecanethiol.

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Background Knock-in mice with the common human BDNF Val66Met polymorphism have impaired trafficking of BDNF mRNA to dendrites. Given evidence that local synapse formation is dependent on dendritic translation of BDNF mRNA, it was hypothesized that loss-of-function Met allele mice would show synaptic deficits both at baseline and in response to ketamine, an NMDA antagonist that stimulates synaptogenesis in prefrontal cortex (PFC). Methods Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were combined with 2-photon laser scanning for analysis of WT, Val/Met, and Met/Met mice both at baseline and in response to a low dose of ketamine. Results Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical dendrites and decrements in apically-targeted excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased, indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met mice the synaptogenic effect of ketamine was markedly impaired, consistent with the idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In parallel behavioral studies we found that the antidepressant response to ketamine in the forced swim test was blocked in Met/Met mice. Conclusions The results demonstrate that expression of the BDNF Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in PFC, suggesting that the therapeutic response to this drug may be attenuated or blocked in depressed patients who carry the loss of function Met allele.

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at 25 °C.14 In this work, we attempted to analyze the complicated oxidation mechanism of the oxygenated compound 3 in watersaturated methylene chloride. During the autoxidation process, several resonances of oxygen-17 enriched species were detected at low frequencies (Figure 3). The resonance absorption at = 11.1 ppm ( /,/2 = 2080 FIz) is characteristic of H2170, and two sharp resonances at = 168.5 and 174.3 ppm can be assigned to H21702. The two latter peaks must correspond to hydrogen peroxide in two different environments. Only the resonance at 174.3 ppm is observed for H2I702 dissolved in dry toluene. The second peak at 168.5 ppm is then probably due to H21702 in

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