Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Heterozygous Mouse Model of Rett Syndrome.

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the () gene. Serotonin reuptake inhibitors improve motor coordination in heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Het mice.

Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin.

Motor skill deficit is a common and invalidating symptom of Rett syndrome (RTT), a rare disease almost exclusively affecting girls during the first/second year of life. Loss-of-function mutations of the methyl-CpG-binding protein2 (MECP2; Mecp2 in rodents) gene is the cause in most patients. We recently found that fluoxetine, a selective serotonin (5-HT) reuptake inhibitor and antidepressant drug, fully rescued motor coordination deficits in Mecp2 heterozygous (Mecp2 HET) mice acting through brain 5-HT.

Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know.

In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks.

Cerebrospinal fluid glutamate changes in functional movement disorders.

The aim of this study was to assess cerebrospinal fluid (CSF) concentrations of specific amino acids using a high-performance liquid chromatography system in a sample of patients with functional movement disorders (FMDs) and in a sample of controls. CSF levels of glutamate were significantly lower in patients with FMD than in controls. This finding argues in favor of glutamatergic dysfunction in the pathophysiology of FMD.

Publisher Correction: Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fluoxetine rescues rotarod motor deficits in Mecp2 heterozygous mouse model of Rett syndrome via brain serotonin.

Motor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linked methyl-CpG-binding protein2 (MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients and Mecp2 mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity. In the present study, we used heterozygous (Het) Mecp2 female and Mecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits.

Ascorbic Acid Route to the Endoplasmic Reticulum: Function and Role in Disease.

Humans cannot synthesize ascorbic acid (AscH) (vitamin C), so deficiencies in dietary AscH cause the life-threatening disease of scurvy and many other diseases. After oral ingestion, plasma AscH concentrations are strictly controlled by transporters, which are required for entry into the cell and into intracellular organelles. Besides its general antioxidant function, AscH is a cofactor for endoplasmic reticulum (ER)-localized collagen hydroxylases.

Neonatal corticosterone mitigates autoimmune neuropsychiatric disorders associated with streptococcus in mice.

Increased glucocorticoid concentrations have been shown to favor resilience towards autoimmune phenomena. Here, we addressed whether experimentally induced elevations in circulating glucocorticoids mitigate the abnormalities exhibited by an experimental model of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities.

Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling.

The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs).

Endoplasmic Reticulum Oxidative Stress Triggers Tgf-Beta-Dependent Muscle Dysfunction by Accelerating Ascorbic Acid Turnover.

Endoplasmic reticulum (ER) and oxidative stress are two related phenomena that have important metabolic consequences. As many skeletal muscle diseases are triggered by oxidative stress, we explored the chain of events linking a hyperoxidized ER (which causes ER and oxidative stress) with skeletal muscle dysfunction. An unbiased exon expression array showed that the combined genetic modulation of the two master ER redox proteins, selenoprotein N (SEPN1) and endoplasmic oxidoreductin 1 (ERO1), led to an SEPN1-related myopathic phenotype due to excessive signalling of transforming growth factor (TGF)-beta.

Lovastatin fails to improve motor performance and survival in -null mice.

Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome.

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

Unlabelled: Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST.

Mouse aldehyde-oxidase-4 controls diurnal rhythms, fat deposition and locomotor activity.

Aldehyde-oxidase-4 (AOX4) is one of the mouse aldehyde oxidase isoenzymes and its physiological function is unknown. The major source of AOX4 is the Harderian-gland, where the enzyme is characterized by daily rhythmic fluctuations. Deletion of the Aox4 gene causes perturbations in the expression of the circadian-rhythms gene pathway, as indicated by transcriptomic analysis.

Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g.

Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release.

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice.

The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity.

Background: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein α-synuclein (α-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by α-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA).

Objective: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach.

Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task.

Executive functions are an emerging propriety of neuronal processing in circuits encompassing frontal cortex and other cortical and subcortical brain regions such as basal ganglia and thalamus. Glutamate serves as the major neurotrasmitter in these circuits where glutamate receptors of NMDA type play key role. Serotonin and dopamine afferents are in position to modulate intrinsic glutamate neurotransmission along these circuits and in turn to optimize circuit performance for specific aspects of executive control over behavior.

A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia.

Cariprazine is a potential antipsychotic awaiting approval from the US Food and Drug Administration. It is a dopamine D2- and D3-receptor partial agonist, with higher affinity for D3 receptors, as opposed to the D2 antagonism of most older antipsychotic agents. Like most lipophilic antipsychotics, it undergoes extensive hepatic metabolism by cytochrome P450 (CYP), mainly the highly variable 3A4, with the formation of active metabolites.

Dopamine D1-like and D2-like receptors in the dorsal striatum control different aspects of attentional performance in the five-choice serial reaction time task under a condition of increased activity of corticostriatal inputs.

We investigated the interaction between the corticostriatal glutamatergic afferents and dopamine D1-like and D2-like receptors in the dorsomedial striatum (dm-STR) in attention and executive response control in the five-choice serial reaction time (5-CSRT) task. The competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) injected in the mPFC impaired accuracy and increased premature and perseverative responding, raising GLU, DA, and GABA release in the dm-STR. The D1-like antagonist SCH23390 injected in the dm-STR reversed the CPP-induced accuracy deficit but did not affect the increase in perseverative responding.

Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine.

Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons.

Distinct Changes in CREB Phosphorylation in Frontal Cortex and Striatum During Contingent and Non-Contingent Performance of a Visual Attention Task.

The cyclic-adenosine monophosphate response element-binding protein (CREB) family of transcription factors has been implicated in numerous forms of behavioral plasticity. We investigated CREB phosphorylation along some nodes of corticostriatal circuitry such as frontal cortex (FC) and dorsal (caudate-putamen, CPu) and ventral (nucleus accumbens, NAC) striatum in response to the contingent or non-contingent performance of the five-choice serial reaction time task (5-CSRTT) used to assess visuospatial attention. Three experimental manipulations were used; an attentional performance group (contingent, "master"), a group trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished (non-contingent, "yoked") and a control group matched for food deprivation and exposure to the test apparatus (untrained).

Three-dimensional self-organizing neural architectures: a neural stem cells reservoir and a system for neurodevelopmental studies.

Complex microenvironmental stimuli influence neural cell properties. To study this, we developed a three-dimensional (3-D) neural culture system, composed of different populations including neurons, astrocytes, and neural stem cells (NSCs). In particular, these last-mentioned cells represent a source potentially exploitable to test drugs, to study neurodevelopment and cell-therapies for neuroregenerations.

Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism.

Impairment of mitochondrial function might contribute to oxidative stress associated with neurodegeneration in amyotrophic lateral sclerosis (ALS). Glutamate levels in tissues of ALS patients are sometimes altered. In neurons, mitochondrial metabolism of exogenous glutamine is mainly responsible for the net synthesis of glutamate, which is a neurotransmitter, but it is also necessary for the synthesis of glutathione, the main endogenous antioxidant.

Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex.

Rationale: Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits.

Objectives: We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed.