Neuroscience
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Comparative Study
The role of metabotropic glutamate receptors in regulation of striatal proenkephalin expression: implications for the therapy of Parkinson's disease.
Overactivity of the striatopallidal pathway, associated with an enhancement of enkephalin expression, has been suggested to contribute to the development of parkinsonian symptoms. The aim of the present study was to examine whether the blockade of group I metabotropic glutamate receptors: subtypes 1 and 5 (mGluR1/5), or stimulation of group II: subtypes 2 and 3 (mGluR2/3) may normalize enkephalin expression in the striatopallidal pathway in an animal model of parkinsonism. The proenkephalin mRNA level measured by in situ hybridization in the striatum was increased by pretreatments with haloperidol (1.5 mg/kg s.c., three times, 3 h apart). ⋯ None of the abovementioned antagonists of mGluR1 and mGluR5 per se influenced the proenkephalin expression. Differential effects were induced by agonists of the group II mGluRs, viz. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine administered intraventricularly (3 times at 0.1-0.2 microg/4 microl, 3 h apart) increased both the normal and haloperidol-increased proenkephalin mRNA level, whereas (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate injected intrastriatally (3 times at 15 microg/0.5 microl, 3 h apart) was ineffective. The present study indicates that the blockade of striatal glutamate receptors belonging to the group I (mGluR1 and mGluR5) but not stimulation of the group II mGluRs may normalize the function of the striatopallidal pathway in an animal model of parkinsonism, which may be important for future antiparkinsonian therapy in humans.
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The molecular mechanisms of the mammalian circadian clock located in the suprachiasmatic nucleus have been essentially studied in nocturnal species. Currently, it is not clear if the clockwork and the synchronizing mechanisms are similar between diurnal and nocturnal species. Here we investigated in a day-active rodent Arvicanthis ansorgei, some of the molecular mechanisms that participate in the generation of circadian rhythmicity and processing of photic signals. ⋯ This study demonstrates that light exposure during the subjective night has opposite effects on the expression of the clock genes Per1 and Per2 compared with that of Cry2. These differential effects can participate in photic resetting of the circadian clock. Our data also indicate that the molecular mechanisms underlying circadian rhythmicity and photic synchronization share clear similarities between diurnal and nocturnal mammals.
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beta-Catenin plays a pivotal role in Wnt signaling during embryogenesis and is a component of adherens junctions. Since targeted disruption of the beta-catenin gene is lethal at gastrulation we have used a D6-Cre mouse line for conditional inactivation of beta-catenin in the mouse cerebral cortex and hippocampus after embryonic day (E) 10.5. ⋯ Severe abnormalities in the organization of the neuroepithelium are observed that include disrupted interkinetic nuclear migration, loss of adherens junctions, impaired radial migration of neurons toward superficial layers and decreased cell proliferation after E15.5. At newborn stage, a premature disassembly of the radial glial scaffold and increased numbers of astrocytes are found in the cortex.
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Disruption of the glucocorticoid negative feedback system is observed in approximate one half of human depressives, and a similar condition is induced in animals by chronic stress. This disruption is thought to involve down-regulation of glucocorticoid receptors (GRs) in the feedback sites of the brain. However, the responsible site of the brain has not been well elucidated. ⋯ In addition, when DEX was injected systemically to the chronically stressed rats, the suppressive response to DEX was significantly attenuated. These results suggest that the abnormal changes in GRs in the higher centers of the hypothalamo-pituitary-adrenal axis are involved in the chronic stress-induced attenuation of the feedback. Since dysfunction of the PFC or hippocampus is implicated in the pathogenesis of depression, the present findings would help to understand the mechanisms underlying the disrupted feedback system and its relation to brain dysfunction in depression.
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We investigated interactions of an anesthetic barbiturate, pentobarbital, with non-ligand gated channels and identified inhibitory synaptic transmission in thalamic neurons. Using whole cell voltage-clamp, current-clamp and single channel recording techniques in rat ventrobasal neurons of slices and dispersed preparations, we determined the mechanisms of pentobarbital actions on ionic currents and inhibitory postsynaptic currents (IPSCs), mediated by aminobutyric acid (GABA). We investigated pentobarbital effects on intrinsic currents using hyperpolarizing voltage commands from rest and tetrodotoxin blockade of action potentials. ⋯ The concentration-response relationships for pentobarbital effects on the intrinsic currents and IPSCs overlapped, implying multiple sites of action and possible redundancy in anesthetic mechanisms. This is the first study to show that an i.v. anesthetic modulates the intrinsic currents, Ih, IKir, and Ileak, as well as IPSC time course in the same neurons. These effects likely underlie inhibition in thalamocortical neurons during pentobarbital anesthesia.