Systemic application of AAV vectors targeting GFAP-expressing astrocytes in Z-Q175-KI Huntington's disease mice.

Huntington's disease (HD) affects both neurons and astrocytes. To target the latter and to ensure brain-wide transgene expression, adeno-associated viral (AAV) vectors can be administered intravenously, as AAV vectors cross the blood-brain barrier (BBB) and enable preferential transduction of astrocytes due to their close association with blood vessels. However, there is a possibility that the subclass of GFAP-expressing astrocytes performs a distinct role in HD and reacts differently to therapeutic measures than the rest of the astrocytes. The gfaABC1D promoter allows specific targeting of the GFAP-expressing astrocytes (~25% of S100ß-expressing astrocytes). We have examined the expression of three different transgenes (GCaMP6f, Kir4.1 and GLT1) and tested the effects of the AAV serotypes 9 and rh8. The AAV vectors were injected into the tail vein of 1-year-old homozygous Z-Q175-KI HD mice and their wild-type (WT) littermates. At this age, HD mice exhibit motor symptoms, including pronounced hypokinesia and circling behaviour. The expression times ranged from 3 to 6weeks. The target cell population was defined as the cells expressing S100ß in addition to GFAP. Viewfields in the dorsal striatum and the overlaying cortex were evaluated and the transduction rate was defined as the percentage of target cells that expressed the reporter transgene (enhanced green fluorescent protein, EGFP, or Tomato). In all cases, the transduction rate was higher in the cortex than in the striatum. AAV9 was more efficient than AAVrh8. One of the injected constructs (AAV9-gfaABC1D-GLT1-Tomato) was tested for the first time. GLT1, the principal astrocytic glutamate transporter, is deficient in HD and therefore considered as a potential target for gene therapy. At a dose of 1.86×1011 vector genome (vg) per animal, the fraction of GLT1-Tomato+ cells in the striatum and the cortex amounted to 30% and 49%, respectively. In individual Tomato+ HD astrocytes, treatment with the GLT1 vector increased the level of GLT1 immunofluorescence by 21% compared to the HD control. The described approach offers new and interesting opportunities to examine the pathophysiological consequences of brain-wide transgene expression in a specific astrocyte subpopulation.

Heat and cold stress increases the risk of paroxysmal supraventricular tachycardia.

Paroxysmal supraventricular tachycardia (PSVT) is a common arrhythmia in adults. Its occurrence depends on the presence of the reentry circuit and the trigger of the paroxysm. Stress, emotional factors, and comorbidities favour the occurrence of such an episode. We hypothesized that the occurrence of PSVT follows extreme thermal episodes. The retrospective analysis was based on the data collected from three hospital emergency departments in Poland (Olsztyn, Radom, and Wroclaw) involving 816 admissions for PSVT in the period of 2016-2021. To test the hypothesis, we applied the Universal Climate Thermal Index (UTCI) to objectively determine exposure to cold or heat stress. The risk (RR) for PSVT increased to 1.37 (p = 0.006) in cold stress and 1.24 (p = 0.05) in heat stress when compared to thermoneutral conditions. The likelihood of PSVT during cold/heat stress is higher in women (RR = 1.59, p< 0.001 and RR = 1.36, p = 0.024, respectively) than in men (RR = 0.64 at p = 0.088 and RR = 0.78, p = 0.083, respectively). The susceptibility for PSVT was even higher in all groups of women after exclusion of perimenopausal group of women, in thermal stress (RR = 1.74, p< 0.001, RR = 1.56, p = 0.029, respectively). Females, particularly at the perimenopausal stage and men irrespective of age were less likely to develop PSVT under thermal stress as compared to thermoneutral conditions. Progress in climate change requires searching for universal methods and tools to monitor relationships between humans and climate. Our paper confirms that the UTCI is the universal tool describing the impact of thermal stress on the human body and its high usefulness in medical researches.

Monoamines block kainate- and carbachol-induced gamma-oscillations but augment stimulus-induced gamma-oscillations in rat hippocampus in vitro.

Monoamines are implicated in a cognitive processes in a variety of brain regions, including the hippocampal formation, where storage and retrieval of information are facilitated by synchronous network activities. We have investigated the effects of norepinephrine, serotonin, and dopamine on carbachol-, kainate-, and stimulus-induced hippocampal gamma-oscillations employing combined extra- and intracellular recordings. Monoamines dose-dependently and reversibly suppressed kainate- and carbachol-induced gamma-oscillations while increasing the frequency. The effect of serotonin was mimicked by fenfluramine, which releases serotonin from presynaptic terminals. Forskolin also suppressed kainate- and carbachol-induced gamma-oscillations. This effect was mimicked by 8-Br-cAMP and isoproterenol, an agonist of noradrenergic beta-receptor suggesting that the monoamines-mediated suppression of these oscillations could involve intracellular cyclic adenosine 3',5'-cyclic monophosphate (AMP). By contrast, stimulus-induced gamma-oscillations were dose-dependently augmented in power and duration after monoamines application. Intracellular recordings from pyramidal cells revealed that monoamines prolonged the stimulus-induced depolarization and membrane potential oscillations. Stimulus-induced gamma-oscillations were also suppressed by isoproterenol, the D1 agonist SKF-38393 forskolin, and 8-Br-cAMP. This suggests that the augmentation of stimulus-induced gamma-oscillations by monoamines involves--at least in part-different classes of cells than in case of carbachol- and kainate-induced gamma-oscillations.