Differential Patterns of Synaptotagmin7 mRNA Expression in Rats with Kainate- and Pilocarpine-Induced Seizures

Previous studies in rat models of neurodegenerative disorders have shown disregulation of striatal synaptotagmin7 mRNA. Here we explored the expression of synaptotagmin7 mRNA in the brains of rats with seizures triggered by the glutamatergic agonist kainate (10 mg/kg) or by the muscarinic agonist pilocarpine (30 mg/kg) in LiCl (3 mEq/kg) pre-treated (24 h) rats, in a time-course experiment (30 min - 1 day). After kainate-induced seizures, synaptotagmin7 mRNA levels were transiently and uniformly increased throughout the dorsal and ventral striatum (accumbens) at 8 and 12 h, but not at 24 h, followed at 24 h by somewhat variable upregulation within different parts of the cerebral cortex, amigdala and thalamic nuclei, the hippocampus and the lateral septum. By contrast, after LiCl/pilocarpine-induced seizures, there was a more prolonged increase of striatal Synaptotagmin7 mRNA levels (at 8, 12 and 24 h), but only in the ventromedial striatum, while in some other of the aforementioned brain regions there was a decline to below the basal levels. After systemic post-treatment with muscarinic antagonist scopolamine in a dose of 2 mg/kg the seizures were either extinguished or attenuated. In scopolamine post-treated animals with extinguished seizures the striatal synaptotagmin7 mRNA levels (at 12 h after the onset of seizures) were not different from the levels in control animals without seizures, while in rats with attenuated seizures, the upregulation closely resembled kainate seizures-like pattern of striatal upregulation. In the dose of 1 mg/kg, scopolamine did not significantly affect the progression of pilocarpine-induced seizures or pilocarpine seizures-like pattern of striatal upregulation of synaptotagmin7 mRNA. In control experiments, equivalent doses of scopolamine per se did not affect the expression of synaptotagmin7 mRNA. We conclude that here described differential time course and pattern of synaptotagmin7 mRNA expression imply regional differences of pathophysiological brain activation and plasticity in these two models of seizures

Walking cadence (steps/min) and intensity in 21-40 year olds: CADENCE-adults

Background: Previous studies have reported that walking cadence (steps/min) is associated with absolutely-defined intensity (metabolic equivalents; METs), such that cadence-based thresholds could serve as reasonable proxy values for ambulatory intensities.Purpose: To establish definitive heuristic (i.e., evidence-based, practical, rounded) thresholds linking cadence with absolutely-defined moderate (3 METs) and vigorous (6 METs) intensity.Methods: In this laboratory-based cross-sectional study, 76 healthy adults (10 men and 10 women representing each 5-year age-group category between 21 and 40 years, BMI = 24.8 +/- 3.4 kg/m 2 ) performed a series of 5-min treadmill bouts separated by 2-min rests. Bouts began at 0.5 mph and increased in 0.5 mph increments until participants: 1) chose to run, 2) achieved 75% of their predicted maximum heart rate, or 3) reported a Borg rating of perceived exertion > 13. Cadence was hand-tallied, and intensity (METs) was measured using a portable indirect calorimeter. Optimal cadence thresholds for moderate and vigorous ambulatory intensities were identified using a segmented regression model with random coefficients, as well as Receiver Operating Characteristic (ROC) models. Positive predictive values (PPV) of candidate heuristic thresholds were assessed to determine final heuristic values.Results: Optimal cadence thresholds for 3 METs and 6 METs were 102 and 129 steps/min, respectively, using the regression model, and 96 and 120 steps/min, respectively, using ROC models. Heuristic values were set at 100 steps/min (PPV of 91.4%), and 130 steps/min (PPV of 70.7%), respectively.Conclusions: Cadence thresholds of 100 and 130 steps/min can serve as reasonable heuristic thresholds representative of absolutely-defined moderate and vigorous ambulatory intensity, respectively, in 21-40 year olds. These values represent useful proxy values for recommending and modulating the intensity of ambulatory behavior and/or as measurement thresholds for processing accelerometer data.Peer reviewedCommunity Health Sciences, Counseling and Counseling Psycholog

Glycine receptor autoantibodies disrupt inhibitory neurotransmission

Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here, purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome, and glycine receptor autoantibodies, were observed to disrupt profoundly glycinergic neurotransmission. In whole-cell patch clamp recordings from cultured rat spinal motor neurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-d-aspartate (NMDA) receptors, affect whole cell currents only after several hours incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalization of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 min of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors

Block of Thalamic T-Type Ca(2+) Channels by Ethosuximide Is Not the Whole Story

On the basis of more than a decade of studies on the cellular effects of ethosuximide, currently, the most prudent view is that together with a block of the low threshold, T-type Ca(2)(+) current, a reduction both of the noninactivating Na(+) current, and the Ca(2)(+)-activated K(+) current in thalamic and cortical neurones contribute to the overall therapeutic action of this antiabsence medicine

Size and shape of the caudate nucleus in individuals with bipolar affective disorder

OBJECTIVE: The caudate nucleus (CN) is a crucial component of the ventral striatum, which is part of a prefrontal-striatal-thalamic circuit that is modulated by limbic structures to subserve emotional processing. Bipolar disorder is thought to be underpinned by dysfunctional anterior limbic networks, although MRI studies examining the CN have shown equivocal results. As gross volumetric analyses may not detect subtle regional change, we aimed to clarify the role of the CN in bipolar disorder by undertaking shape analysis to detect regional reductions. METHODS: The CN was manually traced on MRI scans from 27 patients with bipolar-I disorder and 24 matched controls. A non-parametric spherical harmonic shape analysis was undertaken using the SPHARM toolkit. RESULTS: Whilst the left CN volume was consistently larger in the sample, there was no effect of group or gender or significant interactions between these variables. Volume did not correlate with illness duration or lithium dosage, but was larger in those with a history of psychosis at trend level. However, left caudate shape differed significantly between groups, with deflation in an area along the ventromedial surface (connecting to dorsolateral prefrontal regions) in bipolar patients. Psychotic patients showed increases in the dorsal head and body at trend level overall, in regions connecting to medial and orbitofrontal regions. CONCLUSIONS: These findings suggest that subtle rather than gross structural changes occur in the CN, which may not be detectable by volumetric analysis alone, and reflect alterations in specific frontostriatal circuitry in the disorder