Differential Targeting of Brain Stress Circuits With a Selective Glucocorticoid Receptor Modulator.
Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator.
Proc Natl Acad Sci U S A. 2013 Apr 23;
Zalachoras I, Houtman R, Atucha E, Devos R, Tijssen AM, Hu P, Lockey PM, Datson NA, Belanoff JK, Lucassen PJ, Joëls M, de Kloet ER, Roozendaal B, Hunt H, Meijer OC
Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus-pituitary-adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling. HubMed – depression
Organization and function of transmitter release sites at the neuromuscular junction.
J Physiol. 2013 Apr 22;
Meriney SD, Dittrich M
The neuromuscular junction is known as a strong and reliable synapse. It is strong because it releases an excess of chemical transmitter, beyond what is required to bring the postsynaptic muscle cell to threshold. Since the synapse can sustain suprathreshold muscle activation during short trains of action potentials, it is also reliable. The pre-synaptic mechanisms that lead to reliability during short trains of activity have only recently been elucidated. It appears that there are relatively few calcium channels in individual active zones, that channels open with a low probability during action potential stimulation, and that even if channels open, the resulting calcium flux only rarely triggers vesicle fusion. Thus, each synaptic vesicle may only associate with a small number of calcium channels, forming an unreliable single vesicle release site. Strength and reliability of the neuromuscular junction emerges as a result of their assembly from thousands of these unreliable single vesicle release sites. Hence, these synapses are strong while at the same time only releasing a small subset of available docked vesicles during each action potential, thus conserving transmitter release resources. This prevents significant depression during short trains of action potential activity and confers reliability. HubMed – depression
Adenosine A1-receptor activation mediates the developmental shift at layer-5 pyramidal-cell synapses and is a determinant of mature synaptic strength.
J Physiol. 2013 Apr 22;
Kerr MI, Wall MJ, Richardson MJ
During the first postnatal month glutamatergic synapses between layer-5 pyramidal cells in the rodent neocortex switch from an immature state exhibiting high probability of neurotransmitter release, large unitary amplitude and synaptic depression to a mature state with decreased probability of release, smaller unitary amplitude and synaptic facilitation. Using paired recordings, we demonstrate that the developmental shift in release probability at synapses between rat somatosensory layer-5 thick-tufted pyramidal cells is due to a higher and more heterogeneous activation of presynaptic adenosine A1 receptors. Immature synapses under control conditions exhibited distributions of CV, failure rate and release probability that were almost coincident with the A1-receptor blocked condition; however, mature synapses under control conditions exhibited much broader distributions that spanned those of both the A1-receptor agonised and antagonised conditions. Immature and mature synapses expressed A1 receptors with no observable difference in functional efficacy and therefore the heterogeneous A1-receptor activation seen in the mature neocortex is due to increased adenosine concentrations that vary between synapses. Given the central role demonstrated for A1-receptor activation in determining synaptic amplitude and the statistics of transmission between mature layer-5 pyramidal cells, the emplacement of adenosine sources and sinks near the synaptic terminal could constitute a novel form of long-term synaptic plasticity. HubMed – depression