Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation.

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development.

Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.

Background: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice.

Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener.

Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.

Cyclin-dependent kinase-like 5 () deficiency disorder (CDD) is a rare neurodevelopmental disease caused by mutations in the X-linked gene. CDD is characterized by a broad spectrum of clinical manifestations, including early-onset refractory epileptic seizures, intellectual disability, hypotonia, visual disturbances, and autism-like features. The knockout (KO) mouse recapitulates several features of CDD, including autistic-like behavior, impaired learning and memory, and motor stereotypies.

Early-onset brain alterations during postnatal development in a mouse model of CDKL5 deficiency disorder.

Mutations in the CDKL5 gene are the cause of CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset epilepsy, motor impairment, intellectual disability, and autistic features. A mouse model of CDD, the Cdkl5 KO mouse, that recapitulates several aspects of CDD symptomology, has helped to highlight brain alterations leading to CDD neurological defects. Studies of brain morphogenesis in adult Cdkl5 KO mice showed defects in dendritic arborization of pyramidal neurons and in synaptic connectivity, a hypocellularity of the hippocampal dentate gyrus, and a generalized microglia over-activation.

Cardiac Functional and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.

CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental disease that mostly affects girls, who are heterozygous for mutations in the X-linked gene. Mutations in the gene lead to a lack of CDKL5 protein expression or function and cause numerous clinical features, including early-onset seizures, marked hypotonia, autistic features, gastrointestinal problems, and severe neurodevelopmental impairment. Mouse models of CDD recapitulate several aspects of CDD symptomology, including cognitive impairments, motor deficits, and autistic-like features, and have been useful to dissect the role of CDKL5 in brain development and function.

Early Appearance of Dendritic Alterations in Neocortical Pyramidal Neurons of the Ts65Dn Model of Down Syndrome.

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS.

The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome.

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety.

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in the Ts65Dn model of Down syndrome.

Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus-dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology.

Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders.

Flavonoids have long been known to exert benefits in various health problems. Among them, the BDNF mimetic 7,8-Dihydroxyflavone (7,8-DHF) is emerging as a potential treatment for a constellation of brain and body pathologies. During the past 10 years, more than 180 preclinical studies have explored the efficacy of 7,8-DHF in animal models of different pathologies.

Neuroanatomical alterations in higher-order thalamic nuclei of fetuses with Down syndrome.

Objectives: Down syndrome (DS) is a genetic condition characterized by cognitive disability starting from infancy. Children with DS exhibit deficits in several cognitive domains, including executive function, i.e.

Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome.

Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS.

Timing of Treatment with the Flavonoid 7,8-DHF Critically Impacts on Its Effects on Learning and Memory in the Ts65Dn Mouse.

No therapies currently exist for intellectual disability in Down syndrome (DS). In view of its similarities with DS, including learning and memory (L&M) defects, the Ts65Dn mouse model of DS is widely used for the design of therapy. 7,8-dihydroxyflavone (7,8-DHF), a flavonoid that targets the tropomyosin-related kinase B (TrkB) receptor of brain-derived neurotrophic factor (BDNF), exerts positive effects in various brain disease models.

A flavonoid agonist of the TrkB receptor for BDNF improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn mouse model of DS.

Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Reduced neurogenesis and impaired neuron maturation are considered major determinants of altered brain function in DS. Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and neuron maturation should take place as soon as possible.