Relatively little is known about the development of GABAA receptor subunits and their gene expression in mammalian spinal cord. The expression of mRNAs encoding 13 GABAA receptor subunits (alpha 1-6, beta 1-3, gamma 1-3, and delta) in embryonic, postnatal, and adult rat spinal cord and dorsal root ganglia (DRG) cells were studied by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Both techniques revealed the presence of all subunit mRNAs originally found in the rat brain, except for alpha 6, which was not detectable, and delta, which was weakly detected only by RT-PCR. Two anatomically distinctive sets of subunit mRNAs were found by in situ hybridization within the ventricular zone (VZ) and mantle zone (MZ). The trio of alpha 4, beta 1, and gamma 1 subunit mRNAs emerged exclusively in neuroepithelial cells at embryonic day 13 (E13) and remained detectable in the VZ until E17. In the MZ, beta 3 subunit mRNA was first detected at E12, while alpha 2, alpha 3, alpha 5, beta 2, gamma 2, and gamma 3 transcripts appeared at E13. Expressions of the subunit mRNAs in the MZ rapidly increased and expanded in a ventrodorsal sequence from motoneurons to dorsal horn neurons before reaching a peak in the late embryonic/early postnatal period. The mRNA expressions declined during postnatal development, by region-selective depletion, with alpha 4, alpha 5, beta 1, beta 2, gamma 1, and gamma 3 subunit mRNAs becoming barely detectable. In contrast, alpha 2, alpha 3, beta 3, and gamma 2 transcripts persisted into adulthood with distinct anatomical distributions. RT-PCR analysis revealed unique developmental patterns in the intensities of PCR products, most of which were in good agreement with developmental changes in the densities of hybridized mRNA signals. However, RT-PCR amplified minute amounts of mRNAs for alpha 1, alpha 4, alpha 5, beta 1, beta 2, gamma 1, gamma 3, and delta subunits in adults, which were not found in film autoradiograms, but could be detected in a few grain-positive cells in emulsion-dipped sections. DRG cells expressed alpha 2, alpha 3, alpha 5, beta 2, beta 3, and gamma 2 subunit mRNAs during embryogenesis but only alpha 2, beta 3, and gamma 2 subunit mRNAs were reliably detected in the adult.(ABSTRACT TRUNCATED AT 400 WORDS)
A group of 1070 community-living persons aged 65 and over was assessed using the GMS-AGECAT package and other interviews at years 0 and 3. Year 3 interviewers were 'blind' to the findings at year 0, and the prevalence of organic disorders and depression was very similar in both years. According to the results at year 3, minimum and maximum prevalence figures for dementia at year 0 were 2.4% and 3.8% for moderate to severe and 0.4% and 2.4% for mild or early cases, with a best estimate of 3.5% and 0.8%, or 4.3% overall, divided into: senile, Alzheimer's type 3.3%; vascular 0.7%; and alcohol-related 0.3%. The overall incidence of dementia, clinically confirmed by six-year follow-up, was 9.2/1000 per year (Alzheimer type 6.3, vascular 1.9, alcohol related 1.0). Three years later, 72.0% of those with depressive psychosis and 62.3% of those with depressive neurosis were either dead or had some kind of psychiatric illness. Nearly 60% of milder depressive cases (7.2% of the total sample) had either died or developed a chronic mental illness. The outcome of depressive pseudodementias is equivocal so far. Findings at year 3 provide validation of AGECAT computer diagnosis against outcome; organic and depression diagnoses are seen to have important implications for prognosis.
In 1982-1983 a random sample of 1486 people aged 65 years and above was generated from general practitioner lists; 1070 were interviewed in the community using the Geriatric Mental State and a Social History questionnaire. The cohort was followed up by interview 3 years later. At year 3 the diagnostic computer program AGECAT diagnosed 44 incident cases of depression. Information from the depressed group's initial and further interviews was compared with a control group (which excluded cases of affective or organic mental illness). Univariate analysis yielded three factors that were significantly associated with the development of depression 3 years later: a lack of satisfaction with life; feelings of loneliness; and smoking. Multivariate analysis confirmed their independent effects and revealed 2 further factors attaining significance: female gender and a trigger factor, bereavement of a close figure within 6 months of the third-year diagnosis. Some other factors traditionally associated with depression, such as poor housing, marital status and living alone, failed to attain significance as risk factors.
Under typical culture conditions, cerebellar granule cells die abruptly after 17 days in vitro. This burst of neuronal death involves ultrastructural changes and internucleosomal DNA fragmentations characteristic of apoptosis and is effectively arrested by pretreatment with actinomycin‐D and cycloheximide. The level of a 38‐kDa protein in the particulate fraction is markedly increased during age‐induced cell death and by pretreatment with NMDA, which potentiates this cell death. Conversely, the age‐induced increment of the 38‐kDa particulate protein is suppressed by actinomycin‐D and cycloheximide. N‐terminal microsequencing of the 38‐kDa protein revealed sequence identity with glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). A GAPDH antisense oligodeoxyribonucleotide blocks age‐induced expression of the particulate 38‐kDa protein and effectively inhibits neuronal apoptosis. In contrast, the corresponding sense oligonucleotide of GAPDH was completely ineffective in preventing the age‐induced neuronal death and the 38‐kDa protein overexpression. Moreover, the age‐induced expression of the 38‐kDa protein is preceded by a pronounced increase in the GAPDH mRNA level, which is abolished by actinomycin‐D, cycloheximide, or the GAPDH antisense, but not sense, oligonucleotide. Thus, our results suggest that overexpression of GAPDH in the particulate fraction has a direct role in age‐induced apoptosis of cerebellar neurons.
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