Biology subjects

Mayerl, S.

Publications and source records attributed to Mayerl, S..

3 recordsLinked to original sources

bioRxiv2023

Post-ischemic triiodothyronine treatment improves stroke outcome by stabilizing the blood-brain barrier

Thyroid hormones control a variety of processes in the central nervous system and influence its response to different stimuli, such as ischemic stroke. Post-stroke administration of triiodothyronine (T3) has been reported to substantially improve outcomes, but the optimal dosage and time window remain elusive. To this end we investigated the consequences of T3 treatment in an experimental model of ischemic stroke in mice. Our research demonstrated a dose-dependent protective effect of T3 by reducing infarct volumes, with the optimal T3 dosage identified as 25 {micro}g/kg. In addition, we observed a time-dependent effectiveness that was most pronounced when T3 was administered 1 h after transient middle cerebral artery occlusion, with a gradual reduction in efficacy at 4.5 h, and no reduction in infarct volumes when T3 was injected with an 8 h delay. This protective effect persisted for 72 h post-tMCAO, and had accelerated the recovery of motor function by day 3. In-depth investigations further revealed stabilization of the blood-brain barrier, indicated by reduced extravasation of Evans Blue and diminished aquaporin-4 expression, with reduced inflammation and less cell death as underlying reasons. Our findings suggest that thyroid hormones may be a promising intervention for clinical stroke.

neuroscience↗

bioRxiv2022

Triac treatment prevents neurodevelopmental and locomotor impairments in Mct8/Oatp1c1 double knockout mice.

BackgroundPatients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to an insufficient TH transport and action in the CNS. As a therapeutic strategy, application of Triac (3, 5, 3-triiodothyroacetic acid) and Ditpa (3, 5 -diiodo-thyropropionic acid) have been proposed as both thyromimetic compounds are not dependent on MCT8 for cellular entry. Here, we tested and directly compared the thyromimetic actions of Triac versus Ditpa in Mct8/Oatp1c1 double knockout mice (Dko), a mouse model for human MCT8 deficiency. MethodsNewborn Dko mice were daily injected during the first three postnatal weeks with either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) and compared with Wt and Dko mice receiving saline injections. A second cohort of Dko mice was daily injected with Triac (400 ng/g) only between postnatal week 3 and 6. Thyromimetic effects in the CNS and peripheral tissues were monitored at different postnatal time points by immunofluorescence stainings for neural marker proteins, in situ hybridization and quantitative real time PCR. Locomotor performance was assessed in rotarod and hanging wire test. Acute brain slices of Triac treated Dko mice and their respective controls were used for electrophysiological recordings. ResultsOnly Dko mice injected with Triac (400 ng/g) during the first three postnatal weeks showed normalized myelination, differentiation of cortical GABAergic interneurons as well as locomotor performance. Electrophysiological recordings revealed an increased frequencies of cortical spontaneous miniature inhibitory postsynaptic currents in Dko mice and a normalization of this parameter in Triac treated Dko mice. In comparison, treatment of Dko mice with Ditpa at 4000 ng/g during the first three postnatal weeks resulted in normal myelination and cerebellar development but was less effective in restoring neuronal parameters and locomotor function. Finally, Triac was more potent than Ditpa in suppressing Trh and Tshb expression, respectively, and exerts stronger thyromimetic effects in liver and kidneys. ConclusionsIn newborn Dko deficient mice, Triac is highly effective and more efficient than Ditpa in promoting CNS maturation and function. Yet, Triac treatment needs to be initiated directly after birth to achieve the most beneficial effects.

neuroscience↗

bioRxiv2019

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced compared to controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

neuroscience↗