International experience of legal regulation of freedom of speech in the global information society

The article presents the results of the analysis of international legal regulation of the protection of freedom of speech, the right to freedom of expression within the UN and the Council of Europe. A comparative analysis of the definition of the right to express views and beliefs in various international legal acts was made. The case law of the European Court of Human Rights in cases related to the exercise of the right to express one's views and beliefs on the Internet was considered. The analysis of the legislation of foreign countries regulating the right to express views and beliefs online was carried out. The materials of the article are of practical value for scientists and practitioners dealing with the issues of legal regulation of freedom of speech, the right to express views and beliefs, for forecasting and planning scientific research, improving legislation, for higher education teachers in educational activities, as well as for all interested persons

Cell-Autonomous Alterations in Dendritic Arbor Morphology and Connectivity Induced by Overexpression of MeCP2 in Xenopus Central Neurons In Vivo

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Mutations in the MeCP2 gene have been linked to Rett syndrome, a severe X-linked progressive neurodevelopmental disorder, and one of the most common causes of mental retardation in females. MeCP2 duplication and triplication have also been found to affect brain development, indicating that both loss of function and gain in MeCP2 dosage lead to similar neurological phenotypes. Here, we used the Xenopus laevis visual system as an in vivo model to examine the consequence of increased MeCP2 expression during the morphological maturation of individual central neurons in an otherwise intact brain. Single-cell overexpression of wild-type human MeCP2 was combined with time-lapse confocal microscopy imaging to study dynamic mechanisms by which MeCP2 influences tectal neuron dendritic arborization. Analysis of neurons co-expressing DsRed2 demonstrates that MeCP2 overexpression specifically interfered with dendritic elaboration, decreasing the rates of branch addition and elimination over a 48 hour observation period. Moreover, dynamic analysis of neurons co-expressing wt-hMeCP2 and PSD95-GFP revealed that even though neurons expressing wt-hMeCP2 possessed significantly fewer dendrites and simpler morphologies than control neurons at the same developmental stage, postsynaptic site density in wt-hMeCP2-expressing neurons was similar to controls and increased at a rate higher than controls. Together, our in vivo studies support an early, cell-autonomous role for MeCP2 during the morphological differentiation of neurons and indicate that perturbations in MeCP2 gene dosage result in deficits in dendritic arborization that can be compensated, at least in part, by synaptic connectivity changes

The first report of RPSA polymorphisms, also called 37/67 kDa LRP/LR gene, in sporadic Creutzfeldt-Jakob disease (CJD)

<p>Abstract</p> <p>Background</p> <p>Although polymorphisms of <it>PRNP</it>, the gene encoding prion protein, are known as a determinant affecting prion disease susceptibility, other genes also influence prion incubation time. This finding offers the opportunity to identify other genetic or environmental factor (s) modulating susceptibility to prion disease. Ribosomal protein SA (<it>RPSA</it>), also called 37 kDa laminin receptor precursor (LRP)/67 kDa laminin receptor (LR), acts as a receptor for laminin, viruses and prion proteins. The binding/internalization of prion protein is dependent for LRP/LR.</p> <p>Methods</p> <p>To identify other susceptibility genes involved in prion disease, we performed genetic analysis of <it>RPSA</it>. For this case-control study, we included 180 sporadic Creutzfeldt-Jakob disease (CJD) patients and 189 healthy Koreans. We investigated genotype and allele frequencies of polymorphism on <it>RPSA </it>by direct sequencing or restriction fragment length polymorphism (RFLP) analysis.</p> <p>Results</p> <p>We observed four single nucleotide polymorphisms (SNPs), including -8T>C (rs1803893) in the 5'-untranslated region (UTR) of exon 2, 134-32C>T (rs3772138) in the intron, 519G>A (rs2269350) in the intron and 793+58C>T (rs2723) in the intron on the <it>RPSA</it>. The 519G>A (at codon 173) is located in the direct PrP binding site. The genotypes and allele frequencies of the <it>RPSA </it>polymorphisms showed no significant differences between the controls and sporadic CJD patients.</p> <p>Conclusion</p> <p>These results suggest that these <it>RPSA </it>polymorphisms have no direct influence on the susceptibility to sporadic CJD. This was the first genetic association study of the polymorphisms of <it>RPSA </it>gene with sporadic CJD.</p

Магнитно-резонансная панангиография аорты, коронарных и внутренних грудных артерий в вычислительном анатомическом планировании оптимального малоинвазивного маммарокоронарного шунтирования

Backgrond. Efficiency of low-invasive angiosurgical revascularisation techniques essentially depends on precise and individualised anatomic localization of arteries involved to the procedure. In particular when carrying out the lowinvasive mammarocoronary bypass surgery this means the optimal selection of intercostal anatomic approach adjusted to real position of internal thoracic and coronary arteries. Nevertheless the real possibilities of use of the MRI simultaneously with MR-angiography (MRA) for 3D pre-surgical design and personalization of surgical technique in every personal case according to real anatomic relation of coronary and internal thoracic arteries remain underemployed. Both the feasibilities and long-term results of individual virtual design of mammarocoronary bypass surgery based on routine chest MRI and MRA data are not yet studied, and the real efficiency of such approach remains unclear.Aim: comprised first the development of a technique of 3D virtual anatomic design of mammarocoronary bypass surgery basing on the data of simultaneous ssfp-MRA imaging of coronary and internal mammary arteries and on set of chest MRI tomographic images, in order to improve the results of mammarocoronary mini-invasive transthoracic technique of bypass; and second, the technique was briefly evaluated from the one-year follow-up clinical results.Material and Methods. The patient’s material comprised overall 23 persons who were assigned to two groups – first the fourteen (61%) patients of the main group, in whom the low-invasive mammarocoronary bypass surgeru was carried out; and the nine patients (39%) of the comparison group, recruited from earlier cases, in whom the surgical intervention was performed without evaluation of chest MR-angiographic data. The MRI and MR-angiography, later employed for threedimensional quantification of inter-position of heart surface, of anterior descendent coronary artery, of internal mammary artery, of bone, chet wall muscular and catilage structures, comprised chest breath- and ECG-synchronized MRI with detailed imaging of anterior chest wall, intercostal spaces and internal mammary artery, imaging of the heart itself using two- and four-chamber long-axis positions, and pan-angiography of chest aorta and major arteries, including coronary arteries and internal thoracic arteries. The slices were 4–7 mm thin, acquired to matrix 256 × 256 or 256 × 392 voxels, with field of view as big as 30 × 40 cm. From the 3D model of thoracic and coronary arteries the optimal surgical technique was designed in every clinical case basing on critrion of minimal distance between internal thoracic artey and antrior descending artery as rationale for selection of intercostal level for endoscope introduction and location of aretrio-arterial anastomosis between internal thoracic and coronary arteries.Results. The possibilities of individual anatomic adjustment based on MR-angiography of thoracic arteries were evaluated in fourteen patients in whom the mammarocoronary shunts were carried out basing on MRA data, delivering no any occlusion of the shunt during 12.5 ± 2.2 mnths follow- up. As a control group nine patients who underwent mammarocoronay bypass surgery without pre-operational MRI anatomic simulation were employed, in whom in two of nine occlusion of the shunt occured. The anatomic extent of isolation of internal mammary artery was in the group of patients in whom the 3D MRI-based design of surgey was employed as long as 20–35 mm, in average 29 ± 6 mm, whereas in patients without 3D anatomic simulation and design it was over 30 mm in all cases.Conclusion. Thus, the use of simultaneous MRA imaging of coronary and internal mammary arteries significantly improved both technique of mammarocoronary bypassing itself and provided no cases of shunt occlusion during the one-year folow-up.Введение. Эффективность малоинвазивных ангиохирургических вмешательств в большой степени зависит от точной индивидуальной локализации и анатомической характеристики артерий, в частности – при маммарокоронарном шунтировании – от оптимизации хирургического межреберного доступа в зависимости от расположения внутренней грудной и коронарных артерий (как правило, передней нисходящей). Однако возможности магнитно-резонансной томографии (МРТ) и МР-ангиографии (МРА) используются для такой индивидуализации ангиохирургической техники мало. Целесообразность и отдаленные результаты планирования маммарокоронарного шунтирования на основе МРТ и МРА грудной клетки пока не изучены, а эффективность их не доказана.Цель исследования: разработка методики предоперационного выбора оптимального хирургического доступа для наложения малоинвазивного маммарокоронарного шунта у больных ишемической болезнью сердца, а также оценка результатов клинического использования этой методики при годичных сроках наблюденияМатериал и методы. В исследование вошло 23 человека, которые были разделены на 2 группы: основная группа – 14 (60,9%) пациентов, которым выполняли малоинвазивное маммарокоронарное шунтирование (апробация методики); группа сравнения – 9 (39,1%) пациентов, которым ранее вмешательство выполняли без учета результатов панангиографии грудной клетки. Методика получения изображений МРА и МРТ, использованных затем для трехмерной оценки расположения поверхности сердца, передней нисходящей коронарной артерии, внутренней грудной артерии (ВГА), хрящевых, костных и мышечных структур, включала МРТ грудной клетки в аксиальных и корональных плоскостях с синхронизацией по дыханию и ЭКГ, с детальной визуализацией передней стенки, расположения и ширины межреберных промежутков и затем – получение срезов собственно сердца по длинной оси левого желудочка (в двух- и четырехкамерной позициях), а также и по короткой оси. При этом толщина срезов составляла 4–7 мм, изображения записывались в матрицу 256 × 256 или 256 × 392 элемента при размере поля зрения 30 × 40 см. По данным трехмерного сопоставления МРТ сердца и панартериографии аорты и внутренних грудных и коронарных артерий определяли оптимальный доступ для малоинвазивного маммарокоронарного шунтирования – наложения анастомоза внутренней грудной и передней нисходящей артерий.Результаты. При контроле спустя год (12,5 ± 2,2 мес) проходимость шунта сохранялась у всех 14 пациентов основной группы и лишь у 7 из 9 в группе сравнения (p &lt; 0,05 по критерию χ2), у которых ранее вмешательство выполнялось без МР-коронаро- и аортографии. Протяженность участка выделения ВГА составляла у пациентов, которым выполняли планирование по результатам МРА грудной клетки, 20–35 мм, в среднем 29 ± 6 мм, тогда как в группе сравнения, до использования анатомического моделирования, более 30 мм во всех случаях. Воспалительных осложнений (в частности, медиастинита) не было ни у кого. Заключение. Таким образом, риск осложнений, связанный с анатомической вариабельностью прохождения ВГА, минимизируется при планировании на основе МРТ и МРА за счет использования в каждом случае полностью индивидуальной анатомической картины расположения артерий грудной клетки

Vascular regrowth following photodynamic therapy in the chicken embryo chorioallantoic membrane

Photodynamic therapy (PDT) induces damage to the endothelium, which can lead to increased vascular permeability and, under intensive PDT conditions, even to platelet aggregation, vasoconstriction, and blood flow stasis. Eventually, ischemia, hypoxia, and inflammation can occur, resulting in angiogenesis. We studied the sequence of the vascular events after Visudyne®-PDT in the chicken chorioallantoic membrane (CAM) at day 11 of development. Using epi-fluorescence microscopy, we monitored the regrowth of capillaries in the PDT treated area. Immediately after irradiation, the treatment resulted in blood flow arrest. And 24 h post PDT, sprouting of new blood vessels was observed at the edge of the PDT zone. Neovessels looping out from the edge of the PDT zone gave rise to specialized endothelial tip structures guiding the vessels towards the center of the treated area. At 48 h almost all of the treated area was repopulated with functional but morphologically altered vasculature. These observations also showed reperfusion of some of the vessels that had been closed by the PDT treatment. CAM samples were immunohistochemically stained for Ki-67 showing proliferation of endothelial cells in the PDT area. Also, several markers of immature and angiogenic blood vessels, such as αVβ3-integrin, vimentin and galectin-1, were found to be enhanced in the PDT area, while the endothelial maturation marker intercellular adhesion molecule (ICAM)-1 was found to be suppressed. These results demonstrate that the new vascular bed is formed by both neo-angiogenesis and reperfusion of existing vessels. Both the quantitative real-time RT–PCR profile and the response to pharmacological treatment with Avastin®, an inhibitor of angiogenesis, suggest that angiogenesis occurs after PDT. The observed molecular profiling results and the kinetics of gene regulation may enable optimizing combination therapies involving PDT for treatment of cancer and other diseases

Количественная оценка проницаемости гематомиокардиального барьера для полиацетатных комплексов Gd при ишемической и воспалительной патологии миокарда

Purpose. We developed and applied for quantification of microvascular permeability in damaged myocardium a model - based approach employing the dynamic acquisition of magnetic resonance imaging of paramagnetic diffusion to damaged myocardium and kinetic Gjedde-Rutlend-Patlak (GRP) analysis of blood clearance of the contrast concomitantly with it’s rise in the damaged tissue, in ischemic or inflamed tissue.Material and methods. The model is based on the passive gradient-driven diffusion, unidirectional for first minutes after injection of the contrast, used as Gjedd-Rutland-Patlak technique. If the Cmyoc - depicts the concentration of the paramagnetic in the blood, and the Cblood -means the blood level of the contrast agent, whereas the kblood–myocardium – is the index of diffusion of the contrast from blood to myocardium, then assuming the diffusion unidirectional for first minutes post injection we can plot the ratio {(∫Cblood(t)dt) / Cblood} – as abscissa X, and {Cmyoc /Cblood} – as ordinata Y, kblood-myocardium can be obtained then from such linear plot as it’s slope. We substituted the concentrations themselves with the values of intensities of the echo-planar ECG-synchronized scans of the heart and validated this approach with comparison of MRI intensity data over LV cavity to Gd content in blood samples.MRI of the heart with contrast enhancement was carried out using dynamic scannig, after bolus injection of 2 ml of 0.5 M of paramagnetic contrast (Gadoversetamide -TMOptimark) per 10 Kg of BW. TR = 3.4 ms, TE = 1.7 ms, inversion time 176.0 ms, deviation angle = 40 deg, scanning field 38 х 38 cm, slice thickness = 8-10 мм, acqu-sition matrix 256 х 256, or 192 х 192, echo train length = 1. The groups of patients comprised twenty one persons with acute myocardial infarction treated clically successfully with intravenous thrombolysis and coronary stenting and also nine persons with firstly revealed inflammatory myocarditis. Uptake kinetics to the myocardium was imaged using protocols with fat supression for up to 12 minutes after bolus injection and then processed using RadiAnt software (Medixant, Poznan, Polska), and also original software for dynamic data analysis written using MATLAB 6.1 (SCILAB also), with output of plots of MRI signal intensities over time for various myocardial regions and also of GRP plots and calculation of  kblood-myocardium values.Results. The physiological sence of the kblood–myocardiumdiffusion koefficient means this value depicts the clearance of paramagnetic to myocardium, i.e. the amount of blood cleared from the paramagnetic due to paramagnetic’ diffusion to damaged myocardium, per minute, per unit of myocardial volume. The value of the kblood–myocardiumdiffusion koefficient was, respectively, as high as 3.09 ± 1.32 (2.36-11.9) ml/min/100 g of tissue, in myocardial infarction although treated successfully with thrombolysis and stenting (n = 21) and 1.78 ± 0.67 (0.50-2.42) ml/min/100 g of tissue -in inflammatory myocarditis damage of myocardium (n = 9); In normal controls kblood–myocardium was close to zero values and namely as low as 0.09 ± 0.06 (&lt;0.2) (ml/min/100 g of tissue). Use of this dynamic protocol provided highly significant separation of ishemic and iflammatory conditions.Conclusion. Dynamic MRI echo-planar ECG-synchro-nised contrast-enhanced echo-planar study of the heart can be successfully carried out using both high- and middle-field MRI scanner. The model-based indexes of diffusion of paramagnetic to the infarction or inflammation are significantly different and deliver additional object-based characteristics of the vascular permeability of the damaged haematomyocardial barrier.Цель исследования: разработать и апробировать в клинике методику количественного расчета сосудистой проницаемости гистогематического барьера миокарда для контраста-парамагнетика на основе математической модели Гьедде-Рутланда-Патлака (ГРП) с оценкой роста содержания контраста в миокарде и его клиренса из крови по данным динамической МРТ.Материал и методы. В основе модели накопления парамагнетика в поврежденном миокарде - принцип Гьедде-Рутланд-Патлака (1977). Если Смиок - содержание контраста в миокарде, Скровь - содержание в крови, а ккрть_мтрд - показатель скорости диффузии “кровь-миокард”, считая транспорт парамагнетика однонаправленным в течение первых минут после инъекции, то откладывая {(∫Cкровь(t)dt) / Cкровь} по оси X, а {Cмиок /Cкровь} -по оси Y, kкровь–миокард получается тогда как линейный наклон такого графика.Были обследованы пациенты с острым инфарктом миокарда с успешным тромболизисом (n = 21) и впервые выявленной воспалительной патологией (n = 9). МРТ с парамагнитным контрастным усилением проводилась с помощью динамического протокола FFE1.7.ssfp330k МР-томографа Toshiba Titan Vantage. Динамика поглощения парамагнетика миокардом в ишемических региогнах фиксировалась при введении 2 мл 0,5 M раствора гадоверсетамида на 10 кг массы тела с помощью быстрого протокола в матрицу 256 х 256 элементов изображения, с показателями: время повторения TR = 3,4 мс, время эхо TE = 1,7 мс, время инверсии 176,0 мс, угол отклонения 40°, область сканирования 38 х 38 см, толщина среза 8-10 мм, матрица записи 192 х 192 или 256 х 256, при однократном усреднении, показателе длины эхо (echo train length) равном 1, собственно длительность записи группы из 4 срезов в средней трети левого желудочка 210-300 мс. Запись данных велась на протяжении до 12 мин с частотой 1 кадр в 30 с и затем обрабатывалась с помощью программы RadiAnt (Medixant, Познань, Польша), а также оригинальной программы динамического анализа на MATLAB и SCILAB с построением зависимостей содержания контраста в крови и миокарде от времени, графика ГРП и расчетом показателя kкровь-миокардРезультаты. Физиологический смысл показателя ккровь-миокард в том, что эта величина представляет собой клиренс крови по Gd-ДТПА в миокард, т.е. количество крови, очищаемое от парамагнетика за минуту единицей объема ткани миокарда. Показатель ккровь -миокард составил в зависимости от характера патологии: у пациентов с острым инфарктом миокарда с успешным тромболизистом и ЧКВ (n = 21) 3,09 ± 1,32 (2,3611,9) мл/мин/100 г ткани, тогда как у пациентов с воспалительными поражениями - хроническим миокардитом в стадии обострения или впервые выявленным острым миокардитом (n = 9) 1,78 ± 0,67 (0,50-2,42) мл/мин/100 г ткани. В норме ккровь-миокард слабо отличался от нулевых величин и составлял 0,09 ± 0,06 (&lt;0,2) (мл/мин/100 г ткани). Использование динамического протокола позволило высокодостоверно дифференцировать ишемическое и воспалительное поражение.Заключение. Динамическое МРТ-исследование сердца с парамагнитным контрастным усилением может быть успешно выполнено с помощью как высокопольного, так и среднепольного МР-томографа. Получаемые при математическом моделировании показатели диффузии парамагнетика в ткань ишемического повреждения и воспалительного некоронарогенного очага значительно различаются в зависимости от характера процесса и позволяют получить дополнительную объективную характеристику сосудистой проницаемости пораженного гематомиокардиального барьера

Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy

<p>Abstract</p> <p>Background</p> <p>Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1) Strength of long-term potentiation (LTP), 2) Strength of long-term depression (LTD), 3) Relative inhibition levels (Inhibition), and 4) Excitatory connectivity levels (Connectivity).</p> <p>Results</p> <p>To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties.</p> <p>Conclusions</p> <p>Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.</p

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism

The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation

Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities