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The site of action of the antispastic drug baclofen has long been considered to reside in the spinal cord although supraspinal effects have also been reported. This beta-chlorophenyl derivative of the neurotransmitter gamma-aminobutyric acid (GABA) depresses both monosynaptic and polysynaptic transmission in the cord possibly through a decrease in transmitter release rather than by any antagonism at postsynaptic receptors. Recently, baclofen has been shown to be a selective ligand for a bicuculline-insensitive GABA receptor (GABAB) site that occurs widely in the mammalian central nervous system including the spinal cord. The apparent importance of the cord in the therapeutic effects of this drug prompted us to ask whether they involve GABAB site activation. As an initial step we have located these receptors by autoradiography, comparing them with classical GABAA sites. We report here that GABAB sites, unlike GABAA sites, are present in high concentrations in laminae I, II, III and IV of the dorsal horn and that after the neonatal administration of capsaicin this binding is reduced by 40-50%.

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A BS TRACT: Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [ 11 C]UCB-J, [ 11 C]SA-4503, and [ 18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [ 11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [ 11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [ 11 C]SA-4503 and [ 18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [ 11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.

GABAB binding sites in rat spinal cord have been detected by receptor autoradiography using 3H-GABA in the presence of isoguvacine. The sites could be demonstrated throughout the spinal cord grey matter. The maximum concentration of GABAB sites occurred in lamina II with substantial amounts in other laminae of the dorsal horn. Much lower levels were detected in the ventral horn. Unilateral rhizotomy reduced the number of GABAB sites in the dorsal horn without affecting levels in the ventral horn. The greatest reduction occurred in lamina II with 18% loss 2 days after surgery, 23% after 4 days, 25% after 6 days, and 48% after 15 days. The change after 15 days was comparable to that produced 4 months after neonatal capsaicin administration (50 mg/kg). The only apparent difference between rhizotomy and capsaicin treatment occurred in lamina IV, where rhizotomy produced a greater reduction than capsaicin. 3H-Neurotensin binding in sections from the same animals was unaltered after rhizotomy, indicating a lack of change in the populations of neurons containing neurotensin-binding sites. This would support the view that up to 50% of GABAB binding sites are located on nerve terminals. The greater reduction in lamina IV after rhizotomy would suggest that GABAB sites may be present on large-diameter afferent fibres that terminate in this region as well as on smaller-diameter C and A delta fibres.

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Identifying individuals before the onset of overt symptoms is a key prerequisite for the prevention of Alzheimer's disease (AD). A wealth of data reports dysregulated microRNA (miRNA) expression in the blood of individuals with AD, but evidence in individuals at subclinical stages is sparse. In this study, a qPCR analysis of a prioritised set of 38 candidate miRNAs in the blood of 830 healthy individuals from the CHARIOT PRO cohort (West London, UK) was undertaken. Here, we identified six differentially expressed miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A pathway enrichment analysis for the six miRNAs indicated involvement of apoptosis and inflammation, relevant in early AD stages. Subsequently, we used whole genome sequencing (WGS) data from 750 individuals from the AD Neuroimaging Initiative (ADNI) to perform a genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF concentrations of phosphorylated-tau, total-tau, amyloid-β42 and soluble-TREM2 and BACE1 activity. Our analysis revealed 24 SNPs within MIR29C to be associated with CSF levels of amyloid-β42 and soluble-TREM2 and BACE1 activity. Our study shows the potential of a six-miRNA set as diagnostic blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within MIR29C suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.