Neuroscience
-
Comparative Study
Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease.
Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone and 17beta-estradiol are synthesized by cytochrome P450s from endogenous cholesterol. We previously reported a new cytochrome P450 enzyme, CYP7B, highly expressed in rat and mouse brain that metabolizes DHEA and related steroids by hydroxylation at the 7alpha position. Such 7-hydroxylation can enhance DHEA bioactivity in vivo. ⋯ We also measured CYP7B expression in Alzheimer's disease (AD). CYP7B mRNA was significantly decreased (approximately 50% decline; P<0.05) in dentate neurons from AD subjects compared with controls. A decline in CYP7B activity may contribute the loss of effects of DHEA with ageing and perhaps to the pathophysiology of AD.
-
Comparative Study
The rodent amygdala contributes to the production of cannabinoid-induced antinociception.
The amygdala is a temporal lobe region that is implicated in emotional information processing. The amygdala also is associated with the processing and modulation of pain sensation. Recently, we demonstrated that in nonhuman primates, the amygdala is necessary for the full expression of cannabinoid-induced antinociception [J Neurosci 21 (2001) 8238]. ⋯ In rats treated with intra-CeA muscimol, however, these effects of WIN55,212-2 were significantly reduced. The results constitute the first causal data demonstrating the necessity of descending pain-modulatory circuitry (of which the CeA is a component) for the full expression of cannabinoid-induced antinociception in the rat. Furthermore, the results complement previous findings suggesting an overlap in neural circuitry activated by opioids and cannabinoids.
-
Comparative Study
Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity.
This study was designed to identify molecular mechanisms by which exercise affects synaptic-plasticity in the hippocampus, a brain area whose function, learning and memory, depends on this capability. We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synaptic-plasticity. In fact, this impact of exercise is exemplified by our finding that BDNF regulates the mRNA levels of two end products important for neural function, i.e. cAMP-response-element binding (CREB) protein and synapsin I. ⋯ The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that although BDNF mediates exercise-induced hippocampal plasticity, additional molecules, i.e. the N-methyl-D-aspartate receptor, calcium/calmodulin protein kinase II and the mitogen-activated protein kinase cascade, modulate its effects. Since these molecules have a well-described association to BDNF action, our results illustrate a basic mechanism through which exercise may promote synaptic-plasticity in the adult brain.
-
The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. ⋯ In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.
-
We have assessed the expression and kinetics of voltage-gated K(+) currents in cardiac dorsal root ganglion (DRG) neurons in rats. The neurons were labelled by prior injection of a fluorescent tracer into the pericardial sack. Ninety-nine neurons were labelled: 24% small (diameter<30 microm), 66% medium-sized (diameter 30 microm>.48 microm) and 10% large (>48 microm) neurons. ⋯ All three K(+) current components (I(As), I(Af) and I(K)) were present in every small and medium-sized cardiac DRG neuron. We suggest that at hyperpolarized membrane potentials the fast reactivating I(As) current limits the action potential firing rate of cardiac DRG neurons. At depolarised membrane potentials the I(Af) K(+) current, the reactivation of which is very slow, does not oppose the firing rate of cardiac DRG neurons.