Neuroscience
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Na(+) currents were recorded using patch-clamp techniques from small-diameter (<25 micrometers) dorsal root ganglion neurons, cultured from adult rats (>150 g). Late Na(+) currents maintained throughout long-duration voltage-clamp steps (>/=200 ms) were of two types: a low-threshold, tetrodotoxin-sensitive (TTX-s) current that was largely blocked by 200 nM TTX, and a high-threshold, TTX-resistant (TTX-r) current. TTX-s late current was found in approximately 28% (10/36) of small-diameter neurons and was recorded only in neurons exhibiting TTX-s transient current. ⋯ We suggest that TTX-s late sodium current results from channel openings different from those generating transient current. As in large-diameter sensory neurons, TTX-s channels generating late openings may play a key role in controlling membrane excitability. In contrast, a single population of high-threshold TTX-r channels may account for both transient and late TTX-r currents.
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To examine the role of GABA in the respiratory rhythm and pattern generation in neonatal mice, we analyzed the function of the respiratory control system of 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient neonatal mice. In these mutant (GAD67-/-) mice, GABA levels in the brainstem were reduced to about 30% of those in wild-type (GAD67+/+) mice. In in vivo preparations, ventilatory parameters were analyzed by whole body plethysmography and electromyography of intercostal muscles. ⋯ Superfusion of the in vitro GAD67-/- preparation with 10 microM GABA prolonged C4 burst duration and partly restored a normal pattern of inspiration, although the restoration was limited. These results indicate that reduced GABA levels during the perinatal period induce malfunction in the respiratory control system. We suggest that GABAergic transmission is not essential for basic respiratory rhythm generation but plays an important role in the maintenance of regular respiratory rhythm and normal inspiratory pattern in neonatal mice.
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The pathology of Alzheimer's disease includes amyloid-beta peptide aggregation that contributes to degeneration of cholinergic neurons. Even though the underlying molecular mechanisms remain unclear, recent in vitro evidence supports a protective role for estrogens against several neurotoxic agents. Here we report that, in a murine cholinergic cell line (SN56), the massive cell death induced by 1-40 fragment of amyloid-beta peptide was prevented by 17beta-estradiol through a mechanism that may involve estrogen receptor activation. ⋯ However, the receptor was consistently observed also at the nuclear region after estrogen exposure. Overall, these data suggest that estrogen may exert neuroprotective effects against amyloid-beta-induced toxicity by activation of estrogen receptor-mediated pathways. In addition, intracellular estrogen receptors are up-regulated by their cognate hormone even during exposure to neurotoxic agents.
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Comparative Study
The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease.
A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. ⋯ However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.
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Changes in kappa-opioid receptor levels have been implicated in the development of physical dependence upon and withdrawal from the mixed agonist-antagonist opioid, butorphanol. Immunoblotting analysis was performed to determine the levels of kappa- and mu-opioid receptors in brain regions of rats in withdrawal from dependence upon butorphanol or morphine. Physical dependence was induced by a 72 h i.c.v. infusion with either butorphanol or morphine (26 nmol/microl/h). ⋯ These findings contrasted with those from morphine-withdrawal rats, in which the only changes noted were increases in the thalamus and paraventricular thalamus. Changes in the levels of the mu-opioid receptor protein were observed in 11 of 21 brain regions examined in morphine-withdrawal rats, but only in three of 21 in butorphanol-withdrawal rats. These results implicate a substantive and largely unique role for kappa-opioid receptors in mediation of the development of physical dependence upon, and the expression of withdrawal from, butorphanol, as opposed to the prototypical opioid analgesic, morphine.