Neuroscience
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We have investigated effects of letrozole, an aromatase inhibitor, on spatial learning and memory, expression of neural cell adhesion molecules (NCAM) and catecholaminergic neurotransmitters in the hippocampus and cortex of female rats. In the intact model, adult Sprague-Dawley rats were divided into four groups (n=8). Control received saline alone. ⋯ Letrozole had differential effects on noradrenaline and dopamine content in the cortex. It appears that inhibition of estrogen synthesis in the brain may have beneficial effects on spatial memory. We suggest that structural changes such as NCAM expression and catecholaminergic neurotransmitters in the hippocampus and prefrontal cortex may be the neural basis for estrogen-dependent alterations in cognitive functions.
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Although a robust relationship between sleep and increased brain protein synthesis is well-documented, there have been few reports of the effects of local application of a protein synthesis inhibitor (PSI) on sleep. In this study, we compared the effects of local microdialytic administration of the protein synthesis inhibitor, anisomycin (ANI) into the lateral preoptic area (LPOA), a sleep promoting area vs. the perifornical/lateral hypothalamus (PF/LH), a wake and rapid eye movement (REM) sleep-promoting area. ⋯ ANI microdialysis into hippocampus did not affect sleep or waking. These differential effects of local protein synthesis inhibition on sleep support a hypothesis that mechanisms controlling protein synthesis are critically involved in the regulation of both NREM sleep and REM sleep.
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N-methyl-d-aspartate receptors (NMDARs) are critical determinants of bidirectional synaptic plasticity, however, studies of NMDAR function have been based primarily on pharmacological and electrophysiological manipulations, and it is still debated whether there are subunit-selective forms of long-term potentiation (LTP) and long-term depression (LTD). Here we provide ultrastructural analyses of axospinous synapses in cornu ammonis field 1 of hippocampus (CA1) stratum radiatum of transgenic mice with mutations to two key underlying postsynaptic density (PSD) proteins, postsynaptic density protein 95 (PSD-95) and the alpha-isoform of calcium-calmodulin-dependent protein kinase II (alphaCaMKII). Distribution profiles of synaptic proteins in these mice reveal very different patterns of subunit-specific NMDAR localization, which may be related to the divergent phenotypes of the two mutants. ⋯ In an experiment of mutual exclusivity, neither PSD-95 nor alphaCaMKII localization was found to be affected by mutations to the corresponding PSD protein suggesting that they are functionally independent of the other in the regulation of NR2A- and NR2B-containing NMDARs preceding synaptic activity. Consequently, there may exist at least two distinct PSD-95 and alphaCaMKII-specific NMDAR complexes involved in mediating LTP and LTD through opposing signal transduction pathways in synapses of the hippocampus. The contrasting phenotypes of the PSD-95 and alphaCaMKII mutant mice further establish the prospect of an independent and, possibly, competing mechanism for the regulation of NMDAR-dependent bidirectional synaptic plasticity.
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Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine-mediated neurodegeneration in a rodent model of Parkinson's disease. In this study, we examined the neuroprotective effects of BMP7 against MA-mediated toxicity in dopaminergic neurons. ⋯ High doses of MA significantly suppressed beta-gal activity in striatum, suggesting that MA may inhibit BMP7 expression at the terminals of the nigrostriatal pathway. A similar effect was also found in CD1 mice in that high doses of MA suppressed BMP7 mRNA expression in nigra. In conclusion, our data indicate that MA can cause lesioning in the nigrostriatal dopaminergic terminals and that BMP7 is protective against MA-mediated neurotoxicity in central dopaminergic neurons.
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A recently described family of "orphan" receptors, called Mas-related G-protein-coupled receptors (Mrg), is preferentially expressed in small nociceptive neurons of the rodent and human dorsal root ganglia (DRG). Mrg are activated by high affinity peptide fragments derived from the proenkephalin A gene, e.g. BAM22 (bovine adrenal medullary). ⋯ Two other established MrgC agonists (gamma2-melanocyte stimulating hormone and BAM8-22) were ineffective. Thus, BAM22 sensitizes the capsaicin- and heat-induced CGRP release in an apparently MrgC-unrelated way. The sensitization to heat appears unusually resistant against pharmacological interventions and does not involve TRPV1.