tacrolimus and 3-4-dihydroxyphenylglycol

We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated by preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential or the population spike by the delivery of high-frequency stimulation (HFS, a tetanus of 100 pulses at 100 Hz) to the Schaffer collateral-commissural pathway to CA1 neuron synapses was suppressed when group I metabotropic glutamate receptors (mGluRs) were activated prior to the delivery of HFS. LTP induction was also suppressed when CA1 synapses were preconditioned 60 min before HFS by LFS of 1000 pulses at 1 Hz and this effect was inhibited when the test stimulation delivered at 0.05 Hz was either halted or applied in the presence of an antagonist ofN-methyl-d-aspartate receptors, group I mGluRs, or IP3Rs during a 20-min period from 20 to 40 min after the end of LFS. Furthermore, blockade of group I mGluRs or IP3Rs immediately before the delivery of HFS overcame the effects of the preconditioning LFS on LTP induction. These results suggest that, in CA1 neurons, after a preconditioning LFS, activation of group I mGluRs caused by the test stimulation results in IP3Rs activation that leads to a failure of LTP induction.

Topics: Animals; Benzoates; Benzophenanthridines; Biophysics; Boron Compounds; CA1 Region, Hippocampal; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glycine; Guinea Pigs; Immunosuppressive Agents; In Vitro Techniques; Inositol 1,4,5-Trisphosphate Receptors; Long-Term Potentiation; Male; Methoxyhydroxyphenylglycol; Neurons; Tacrolimus

Trafficking of G protein-coupled receptors plays a crucial role in controlling the precise signalling of the receptor as well as its proper regulation. Metabotropic glutamate receptor 1 (mGluR1), a G protein-coupled receptor, is a member of the group I mGluR family. mGluR1 plays a critical role in neuronal circuit formation and also in multiple types of synaptic plasticity. This receptor has also been reported to be involved in various neuropsychiatric diseases. Other than the central nervous system, mGluR1 plays crucial roles in various non-neuronal cells like hepatocytes, skin cells, etc. Although it has been reported that mGluR1 gets endocytosed on ligand application, the events after the internalization of the receptor has not been studied. We show here that mGluR1 internalizes on ligand application. Subsequent to endocytosis, majority of the receptors localize at the recycling compartment and no significant presence of the receptor was noticed in the lysosome. Furthermore, mGluR1 returned to the cell membrane subsequent to ligand-mediated internalization. We also show here that the recycling of mGluR1 is dependent on the activity of protein phosphatase 2A. Thus, our data suggest that the ligand-mediated internalized receptors recycle back to the cell surface in protein phosphatase 2A-dependent manner.

Topics: Ammonium Chloride; Animals; Calcineurin Inhibitors; Cell Line, Tumor; Cell Membrane; Cyclosporine; Endocytosis; HEK293 Cells; Humans; Methoxyhydroxyphenylglycol; Mice; Neuroblastoma; Protein Phosphatase 2; Receptors, Metabotropic Glutamate; RNA, Small Interfering; Tacrolimus; Time Factors; Transfection

Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer's type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer's disease.

Topics: Alzheimer Disease; Animals; CA1 Region, Hippocampal; Calcineurin Inhibitors; Caspase 3; Dendrites; Disease Models, Animal; Disks Large Homolog 4 Protein; Drug Evaluation, Preclinical; Excitatory Postsynaptic Potentials; Guanylate Kinases; Long-Term Synaptic Depression; Male; Membrane Proteins; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Neuroprotective Agents; Phosphorylation; Phosphoserine; Post-Synaptic Density; Protein Processing, Post-Translational; Receptors, AMPA; Receptors, Metabotropic Glutamate; Tacrolimus