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Owing to its anatomical connections, the external cuneate nucleus (ECU) plays a crucial role in processing proprioceptive input from the upper trunk and upper limbs. Here, we studied this dorsal column nucleus post-mortem in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, who had manifested upper trunk and upper limb ataxia. Polyethylene glycol-embedded 100-mum sections stained for lipofuscin pigment and Nissl material, as well as paraffin-embedded Nissl-stained thin sections, revealed serious neuronal loss in the ECU of all live SCA3 patients. As observed in other affected central nervous system structures, the ECU of these individuals displayed an astrogliosis, and some of the few surviving neurons harbored one or even two ataxin-3-immunopositive intranuclear inclusion bodies. The findings of the present study suggest that (1) the ECU is among the consistent targets of the degenerative process underlying SCA3 and (2) interruption of the proprioceptive pathway at the level of the ECU contributes significantly to upper limb and trunk ataxia in SCA3 patients. (C) 2002 Elsevier Science B.V. All rights reserved.

Owing to its anatomical connections, the external cuneate nucleus (ECU) plays a crucial role in processing proprioceptive input from the upper trunk and upper limbs. Here, we studied this dorsal column nucleus post-mortem in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, who had manifested upper trunk and upper limb ataxia. Polyethylene glycol-embedded 100-mum sections stained for lipofuscin pigment and Nissl material, as well as paraffin-embedded Nissl-stained thin sections, revealed serious neuronal loss in the ECU of all live SCA3 patients. As observed in other affected central nervous system structures, the ECU of these individuals displayed an astrogliosis, and some of the few surviving neurons harbored one or even two ataxin-3-immunopositive intranuclear inclusion bodies. The findings of the present study suggest that (1) the ECU is among the consistent targets of the degenerative process underlying SCA3 and (2) interruption of the proprioceptive pathway at the level of the ECU contributes significantly to upper limb and trunk ataxia in SCA3 patients. (C) 2002 Elsevier Science B.V. All rights reserved.

We investigated cell proliferation and cell death in the olfactory epithelium (OE) of mice from birth to maturity using bromodeoxyuridine and terminal deoxynucleotidyl transferase nick end labeling. We show that cell death events and proliferative activity diminish concomitantly with age in the OE. Thus, the age-dependent and coordinate diminution in cell proliferative activity and cell death events may serve to maintain the thickness of the OE as mice mature and age. (C) 1997 Elsevier Science B.V.

We investigated cell proliferation and cell death in the olfactory epithelium (OE) of mice from birth to maturity using bromodeoxyuridine and terminal deoxynucleotidyl transferase nick end labeling. We show that cell death events and proliferative activity diminish concomitantly with age in the OE. Thus, the age-dependent and coordinate diminution in cell proliferative activity and cell death events may serve to maintain the thickness of the OE as mice mature and age. (C) 1997 Elsevier Science B.V.

beta-Amyloid((1-42)) peptide (beta AP((1-42))) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were primarily choline acetyltransferase-immunoreactive (ir), while only minor effects of beta AP((1-42)) were observed on parvalbumin-ir interneurons. These results indicate that the changes in intracellular Ca2+ level elicited by beta AP((1-42)) may contribute to beta-amyloid neurotoxicity, and Ca2+-binding proteins may play an important role in the protection against the neurotoxic effects of beta AP((1-42)).

beta-Amyloid((1-42)) peptide (beta AP((1-42))) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were primarily choline acetyltransferase-immunoreactive (ir), while only minor effects of beta AP((1-42)) were observed on parvalbumin-ir interneurons. These results indicate that the changes in intracellular Ca2+ level elicited by beta AP((1-42)) may contribute to beta-amyloid neurotoxicity, and Ca2+-binding proteins may play an important role in the protection against the neurotoxic effects of beta AP((1-42)).

In this study we examined long-lasting effects mediated by intracellular mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) on two voltage dependent potassium conductances in CA1 pyramidal neurons, i.e. the transient current I(A) and the delayed rectifier, and on the inward rectifier I(Q), a mixed sodium/potassium current. All experiments were carried out in hippocampal slices with the in situ patch clamp technique, in the whole cell mode. Neurons recorded 30 min to 3 h after a brief application of 30 nM corticosterone to slices from adrenalectomized rats, thus saturating MRs and occupying most of the GRs, displayed a large I(Q)-conductance similar to neurons in slices from the sham-operated controls. By contrast, if only MRs or only GRs were activated, the I(Q)-conductance was significantly smaller than for the corticosterone-treated group of cells, indicating that simultaneous activation of both MRs and GRs is necessary to achieve a large I(Q)-conductance. If corticosterone was applied in the presence of a protein synthesis inhibitor, the I(Q) conductance was significantly smaller than in the absence of the inhibitor. Properties of the I(A) and the delayed rectifier were not affected by the various corticosteroid treatments. In conclusion, the data indicate that in particular the I(Q)-conductance is under a gene-mediated control of corticosteroid hormones. The I(Q)-conductance is relatively low when only MRs are activated, as occurs for the rat in the morning under rest, and high when both MRs and GRs are occupied, as occurs at the peak of the circadian cycle and after stress. This finding suggests that MR- and GR-mediated events act in synergism to control the I(Q), thus contributing to regulation of cellular excitability under physiologically relevant conditions.

Pyramidal neurons in the rat CA1 hippocampal area contain intracellular receptors for the steroid hormone corticosterone, and membrane associated alpha- and beta-adrenergic receptors. We compared the effect of noradrenaline (NA) on the synaptically evoked CA1 field potential in adrenalectomized (ADX) rats, where corticosteroid receptors are not occupied, with sham-operated controls. It appeared that the increase in the amplitude of the field potential induced by 10-mu-M NA was more pronounced in slices from ADX rats than in sham operated controls. In vitro application of 30 nM corticosterone (20 min) to slices from ADX rats shifted the NA-evoked increases in synaptic efficacy towards the level of the sham operated rats. The incidence of a secondary population spike after application of NA was increased in slices from ADX rats compared to slices from sham controls or ADX rats treated with corticosterone. Occupation of receptors for corticosterone in the hippocampal CA1 area may therefore potentially lead to suppression of excitability.