Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS. IntroductionMonocarboxylate transporter 8 (MCT8) is a specific thyroid hormone (TH) transporter that facilitates the passage of the prohormone 3,3′,5,5′-tetraiodothyronine (T4; also known as thyroxine) and the receptor active form, 3,3′,5-triiodothyronine (T3), across the plasma membrane (1). MCT8 is encoded by SLC16A2 (hereafter MCT8) located on human chromosome Xq13.2. Inactivating mutations and deletions in MCT8 result in a distinct clinical picture known as Allan-Herndon-Dudley syndrome (AHDS) (2-5).All affected patients manifest a severe form of psychomotor retardation composed of central hypotonia, spastic tetraplegia, lack of speech development, severe intellectual deficits, and global developmental delays. In addition to the pronounced neurological symptoms, patients exhibit characteristic changes in the serum TH profile, with highly elevated T3 and lowered T4 concentrations. Since 2004, more than 45 families with 125 affected individuals have been reported in the literature, and 1% of cases with the diagnosis of X-linked mental retardation have been estimated to be associated with mutations in MCT8 (6). However, by which pathogenic mechanisms MCT8 deficiency causes AHDS remains largely unknown.MCT8 is present in many organs, such as liver, kidneys, pituitary, and thyroid gland, and is also widely expressed in the CNS. Studies in mouse and human brain tissues revealed MCT8 expression in distinct neuronal populations, with the highest mRNA levels in neo-and allocortical structures (e.g., cerebral cor...

An adaptive on-line procedure is presented for autoregressive (AR) modeling of nonstationary multivariate time series by means of Kalman filtering. The parameters of the estimated time-varying model can be used to calculate instantaneous measures of linear dependence. The usefulness of the procedures in the analysis of physiological signals is discussed in two examples: First, in the analysis of respiratory movement, heart rate fluctuation, and blood pressure, and second, in the analysis of multichannel electroencephalogram (EEG) signals. It was shown for the first time that in intact animals the transition from a normoxic to a hypoxic state requires tremendous short-term readjustment of the autonomic cardiac-respiratory control. An application with experimental EEG data supported observations that the development of coherences among cell assemblies of the brain is a basic element of associative learning or conditioning.

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The mechanism of cell transformation by Fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is incompletely understood. The most prevalent activated mutant FLT3 ITD exhibits an altered signaling quality, including strong activation of the STAT5 transcription factor. FLT3 ITD has also been found partially retained as a high-mannose precursor in an intracellular compartment. To analyze the role of intracellular retention of FLT3 for transformation, we have generated FLT3 versions that are anchored in the perinuclear endoplasmic reticulum (ER) by appending an ER retention sequence containing a RRR (R3) motif. ER retention of R3, but not of corresponding A3 FLT3 versions, is shown by biochemical, fluorescence-activated cell sorting, and immunocytochemical analyses. ER anchoring reduced global autophosphorylation and diminished constitutive activation of ERK1/2 and AKT of the constitutively active FLT3 versions. ER anchoring was, however, associated with elevated signaling to STAT3. Transforming activity of the FLT3 D835Y mutant was suppressed by ER anchoring. In contrast, ER-anchored FLT3 ITD retained STAT5-activating capacity and was transforming in vitro and in vivo. The findings highlight another aspect of the different signaling quality of FLT3 ITD: It can transform cells from an intracellular location.

Trained immunity and immune tolerance have been identified as long-term response patterns of the innate immune system. The causes of these opposing reactions remain elusive. Here, we report about differential inflammatory responses of microglial cells derived from neonatal mouse brain to increasing doses of the endotoxin LPS. Prolonged priming with ultra-low LPS doses provokes trained immunity, i.e., increased production of pro-inflammatory mediators in comparison to the unprimed control. In contrast, priming with high doses of LPS induces immune tolerance, implying decreased production of inflammatory mediators and pronounced release of anti-inflammatory cytokines. Investigation of the signaling processes and cell functions involved in these memory-like immune responses reveals the essential role of phosphoinositide 3-kinase γ (PI3Kγ), one of the phosphoinositide 3-kinase species highly expressed in innate immune cells. Together, our data suggest profound influence of preceding contacts with pathogens on the immune response of microglia. The impact of these interactions—trained immunity or immune tolerance—appears to be shaped by pathogen dose.