The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (<i>R</i>)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC

(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC

The Effect of TGF-β1 Reduced Functionality on the Expression of Selected Synaptic Proteins and Electrophysiological Parameters: Implications of Changes Observed in Acute Hepatic Encephalopathy

Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice