Crosslinked Chitosan Nanoparticles with Muco-Adhesive Potential for Intranasal Delivery Applications.

Intranasal drug delivery is convenient and provides a high bioavailability but requires the use of mucoadhesive nanocarriers. Chitosan is a well-established polymer for mucoadhesive applications but can suffer from poor cytocompatibility and stability upon administration. In this work, we present a method to obtain stable and cytocompatible crosslinked chitosan nanoparticles. We used 2,6-pyridinedicarboxylic acid as a biocompatible crosslinker and compared the obtained particles with those prepared by ionotropic gelation using sodium tripolyphosphate. Nanoparticles were tested to evaluate the size and the surface charge, as well as their stability in storage conditions (4 °C), at the nasal cavity temperature (32 °C), and at the body temperature (37 °C). The crosslinked chitosan nanoparticles showed a size around 150 nm and a surface charge of 10.3 mV ± 0.9 mV, both compatible with the intranasal drug administration. Size and surface charge parameters did not significantly vary over time, indicating the good stability of these nanoparticles. We finally tested their cytocompatibility in vitro using SHSY5Y human neuroblastoma and RPMI 2650 human nasal epithelial cells, with positive results. In conclusion, the proposed synthetic system shows an interesting potential as a drug carrier for intranasal delivery.

Creatine deficiency and heart failure.

Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.

Visual Cortex Engagement in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is a family of inherited disorders caused by the progressive degeneration of retinal photoreceptors. There is no cure for RP, but recent research advances have provided promising results from many clinical trials. All these therapeutic strategies are focused on preserving existing photoreceptors or substituting light-responsive elements. Vision recovery, however, strongly relies on the anatomical and functional integrity of the visual system beyond photoreceptors. Although the retinal structure and optic pathway are substantially preserved at least in early stages of RP, studies describing the visual cortex status are missing. Using a well-established mouse model of RP, we analyzed the response of visual cortical circuits to the progressive degeneration of photoreceptors. We demonstrated that the visual cortex goes through a transient and previously undescribed alteration in the local excitation/inhibition balance, with a net shift towards increased intracortical inhibition leading to improved filtering and decoding of corrupted visual inputs. These results suggest a compensatory action of the visual cortex that increases the range of residual visual sensitivity in RP.

Longitudinal Bottom-Up Proteomics of Serum, Serum Extracellular Vesicles, and Cerebrospinal Fluid Reveals Candidate Biomarkers for Early Detection of Glioblastoma in a Murine Model.

Glioblastoma Multiforme (GBM) is a brain tumor with a poor prognosis and low survival rates. GBM is diagnosed at an advanced stage, so little information is available on the early stage of the disease and few improvements have been made for earlier diagnosis. Longitudinal murine models are a promising platform for biomarker discovery as they allow access to the early stages of the disease. Nevertheless, their use in proteomics has been limited owing to the low sample amount that can be collected at each longitudinal time point. Here we used optimized microproteomics workflows to investigate longitudinal changes in the protein profile of serum, serum small extracellular vesicles (sEVs), and cerebrospinal fluid (CSF) in a GBM murine model. Baseline, pre-symptomatic, and symptomatic tumor stages were determined using non-invasive motor tests. Forty-four proteins displayed significant differences in signal intensities during GBM progression. Dysregulated proteins are involved in cell motility, cell growth, and angiogenesis. Most of the dysregulated proteins already exhibited a difference from baseline at the pre-symptomatic stage of the disease, suggesting that early effects of GBM might be detectable before symptom onset.

p75 Neurotrophin Receptor Activation Regulates the Timing of the Maturation of Cortical Parvalbumin Interneuron Connectivity and Promotes Juvenile-like Plasticity in Adult Visual Cortex.

By virtue of their extensive axonal arborization and perisomatic synaptic targeting, cortical inhibitory parvalbumin (PV) cells strongly regulate principal cell output and plasticity and modulate experience-dependent refinement of cortical circuits during development. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates numerous cellular functions; however, its role on cortical circuit development and plasticity remains elusive, mainly because localizing p75NTR expression with cellular and temporal resolution has been challenging. By using RNAscope and a modified version of the proximity ligation assay, we found that p75NTR expression in PV cells decreases between the second and fourth postnatal week, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in vitro and in PV cell networks in vivo causes precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, therefore suggesting that p75NTR expression modulates the timing of maturation of PV cell connectivity in the adolescent cortex. Remarkably, we found that PV cells still express p75NTR in adult mouse cortex of both sexes and that its activation is sufficient to destabilize PV cell connectivity and to restore cortical plasticity following monocular deprivation in vivo Together, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represent a novel tool to foster brain plasticity in adults.SIGNIFICANCE STATEMENT In the cortex, inhibitory, GABA-releasing neurons control the output and plasticity of excitatory neurons. Within this diverse group, parvalbumin-expressing (PV) cells form the larger inhibitory system. PV cell connectivity develops slowly, reaching maturity only at the end of adolescence; however, the mechanisms controlling the timing of its maturation are not well understood. We discovered that the expression of the neurotrophin receptor p75NTR in PV cells inhibits the maturation of their connectivity in a cell-autonomous fashion, both in vitro and in vivo, and that p75NTR activation in adult PV cells promotes their remodeling and restores cortical plasticity. These results reveal a new p75NTR function in the regulation of the time course of PV cell maturation and in limiting cortical plasticity.

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.

Bacterial Toxins and Targeted Brain Therapy: New Insights from Cytotoxic Necrotizing Factor 1 (CNF1).

Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), a cytotoxin produced by Escherichia coli affecting fundamental cellular processes, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and migration. First, we provide an overview of the mechanisms of action of CNF1 in target cells. Next, we focus on the potential use of CNF1 as a pharmacological treatment in central nervous system's diseases. CNF1 appears to impact neuronal morphology, physiology, and plasticity and displays an antineoplastic activity on brain tumors. The ability to preserve neural functionality and, at the same time, to trigger senescence and death of proliferating glioma cells, makes CNF1 an encouraging new strategy for the treatment of brain tumors.

Experience Affects Critical Period Plasticity in the Visual Cortex through an Epigenetic Regulation of Histone Post-Translational Modifications.

During an early phase of enhanced sensitivity called the critical period (CP), monocular deprivation causes a shift in the response of visual cortex binocular neurons in favor of the nondeprived eye, a process named ocular dominance (OD) plasticity. While the time course of the CP for OD plasticity can be modulated by genetic/pharmacological interventions targeting GABAergic inhibition, whether an increased sensory-motor experience can affect this major plastic phenomenon is not known. We report that exposure to environmental enrichment (EE) accelerated the closure of the CP for OD plasticity in the rat visual cortex. Histone H3 acetylation was developmentally regulated in primary visual cortex, with enhanced levels being detectable early in enriched pups, and chromatin immunoprecipitation revealed an increase at the level of the BDNF P3 promoter. Administration of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) to animals reared in a standard cage mimicked the increase in H3 acetylation observed in the visual cortex and resulted in an accelerated decay of OD plasticity. Finally, exposure to EE in adulthood upregulated H3 acetylation and was paralleled by a reopening of the CP. These findings demonstrate a critical involvement of the epigenetic machinery as a mediator of visual cortex developmental plasticity and of the impact of EE on OD plasticity. SIGNIFICANCE STATEMENT: While it is known that an epigenetic remodeling of chromatin structure controls developmental plasticity in the visual cortex, three main questions have remained open. Which is the physiological time course of histone modifications? Is it possible, by manipulating the chromatin epigenetic state, to modulate plasticity levels during the critical period? How can we regulate histone acetylation in the adult brain in a noninvasive manner? We show that the early exposure of rat pups to enriching environmental conditions accelerates the critical period for plasticity in the primary visual cortex, linking this effect to increased histone acetylation, specifically at the BDNF gene level. Moreover, we report that the exposure of adult animals to environmental enrichment enhances histone acetylation and reopens juvenile-like plasticity.

Early environmental therapy rescues brain development in a mouse model of Down syndrome.

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS.

Enriched early life experiences reduce adult anxiety-like behavior in rats: a role for insulin-like growth factor 1.

Early life experiences can affect brain development, contributing to shape interindividual differences in stress vulnerability and anxiety-like behavior. In rodents, high levels of maternal care have long-lasting positive effects on the behavior of the offspring and stress response; post-weaning rearing in an enriched environment (EE) or massage counteract the negative effects of maternal separation or prenatal stressors. We recently found that insulin-like growth factor 1 (IGF-1) is a key mediator of early EE or massage on brain development. Whether early enrichment of experience can induce long-lasting effects on anxiety-like behavior and whether IGF-1 is involved in these effects is not known. We assessed anxiety-like behavior by means of the elevated plus maze in control adult rats and in adult rats subjected to early EE or to massage. We found that both EE and massage reduced adult anxiety-like behavior. Early IGF-1 systemic injections in rat pups reared in standard condition mimic the effects of EE and massage, reducing anxiety-like behavior in the adult; blocking early IGF-1 action in massaged and EE animals prevents massage and EE effects. In EE and IGF-1-treated animals, we assessed the hippocampal expression of glucocorticoid receptors (GRs) at postnatal day 12 (P12) and P60, finding a significantly higher GR expression at P60 for both treatments. These results suggest that IGF-1 could be involved in mediating the long-lasting effects of early life experiences on vulnerability/resilience to stress in adults.

Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome.

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the major animal model for DS, have severe cognitive and synaptic plasticity dysfunctions caused by excessive inhibition in their temporal lobe structures. Here we employed a multidisciplinary approach spanning from the behavioral to the electrophysiological and molecular level to investigate the effects elicited by fluoxetine on cognitive abilities, hippocampal synaptic plasticity and GABA release in adult Ts65Dn mice. We report that a chronic treatment with fluoxetine administered in the drinking water normalizes GABA release and promotes recovery of spatial memory abilities, spatial working memory for alternation, and hippocampal synaptic plasticity in adult Ts65Dn mice. Our findings might encourage new experimental attempts aimed at investigating the potential of fluoxetine for application in the treatment of major functional deficits in adult people with DS.

Stabilized Reversed Polymeric Micelles as Nanovector for Hydrophilic Compounds.

Small hydrophilic drugs are widely used for systemic administration, but they suffer from poor absorption and fast clearance. Their nanoencapsulation can improve biodistribution, targeted delivery, and pharmaceutical efficacy. Hydrophilics are effectively encapsulated in compartmented particles, such as liposomes or extracellular vesicles, which are biocompatible but poorly customizable. Polymeric vectors can form compartmental structures, also being functionalizable. Here, we report a system composed of polymeric stabilized reversed micelles for hydrophilic drugs encapsulation. We optimized the preparation procedure, and calculated the critical micellar concentration. Then, we developed a strategy for stabilization that improves micelle stability upon dilution. We tested the drug loading and delivery capabilities with creatine as a drug molecule. Prepared stabilized reversed micelles had a size of around 130 nm and a negative z-potential around -16 mV, making them functional as a drug carrier. The creatine cargo increased micelle size and depended on the loading conditions. The higher amount of loaded creatine was around 60 µg/mg of particles. Delivery tests indicated full release within three days in micelles with the lower cargo, while higher loadings can provide a sustained release for longer times. Obtained results are interesting and encouraging to test the same system with different drug cargoes.

A Potential Biomarker of Brain Activity in Autism Spectrum Disorders: A Pilot fNIRS Study in Female Preschoolers.

Autism spectrum disorder (ASD) refers to a neurodevelopmental condition whose detection still remains challenging in young females due to the heterogeneity of the behavioral phenotype and the capacity of camouflage. The availability of quantitative biomarkers to assess brain function may support in the assessment of ASD. Functional Near-infrared Spectroscopy (fNIRS) is a non-invasive and flexible tool that quantifies cortical hemodynamic responses (HDR) that can be easily employed to describe brain activity. Since the study of the visual phenotype is a paradigmatic model to evaluate cerebral processing in many neurodevelopmental conditions, we hypothesized that visually-evoked HDR (vHDR) might represent a potential biomarker in ASD females. We performed a case-control study comparing vHDR in a cohort of high-functioning preschooler females with ASD (fASD) and sex/age matched peers. We demonstrated the feasibility of visual fNIRS measurements in fASD, and the possibility to discriminate between fASD and typical subjects using different signal features, such as the amplitude and lateralization of vHDR. Moreover, the level of response lateralization was correlated to the severity of autistic traits. These results corroborate the cruciality of sensory symptoms in ASD, paving the way for the validation of the fNIRS analytical tool for diagnosis and treatment outcome monitoring in the ASD population.

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency.

Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency.

Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8-/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8-/y mice and wild type and DCE-treated Slc6a8-/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD.

IGF-1 restores visual cortex plasticity in adult life by reducing local GABA levels.

The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes.

The amplitude of fNIRS hemodynamic response in the visual cortex unmasks autistic traits in typically developing children.

Autistic traits represent a continuum dimension across the population, with autism spectrum disorder (ASD) being the extreme end of the distribution. Accumulating evidence shows that neuroanatomical and neurofunctional profiles described in relatives of ASD individuals reflect an intermediate neurobiological pattern between the clinical population and healthy controls. This suggests that quantitative measures detecting autistic traits in the general population represent potential candidates for the development of biomarkers identifying early pathophysiological processes associated with ASD. Functional near-infrared spectroscopy (fNIRS) has been extensively employed to investigate neural development and function. In contrast, the potential of fNIRS to define reliable biomarkers of brain activity has been barely explored. Features of non-invasiveness, portability, ease of administration, and low-operating costs make fNIRS a suitable instrument to assess brain function for differential diagnosis, follow-up, analysis of treatment outcomes, and personalized medicine in several neurological conditions. Here, we introduce a novel standardized procedure with high entertaining value to measure hemodynamic responses (HDR) in the occipital cortex of adult subjects and children. We found that the variability of evoked HDR correlates with the autistic traits of children, assessed by the Autism-Spectrum Quotient. Interestingly, HDR amplitude was especially linked to social and communication features, representing the core symptoms of ASD. These findings establish a quick and easy strategy for measuring visually-evoked cortical activity with fNIRS that optimize the compliance of young subjects, setting the background for testing the diagnostic value of fNIRS visual measurements in the ASD clinical population.

Oral Feeding of an Antioxidant Cocktail as a Therapeutic Strategy in a Mouse Model of Rett Syndrome: Merits and Limitations of Long-Term Treatment.

Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. For the first 6-18 months of life, the development of the mostly female patients appears normal. Subsequently, cognitive impairment, motor disturbances, hand stereotypies, epilepsy, and irregular breathing manifest, with previously learned skills being lost. Early mitochondrial impairment and a systemic oxidative burden are part of the complex pathogenesis, and contribute to disease progression. Accordingly, partial therapeutic merits of redox-stabilizing and antioxidant (AO) treatments were reported in RTT patients and Mecp2-mutant mice. Pursuing these findings, we conducted a full preclinical trial on male and female mice to define the therapeutic value of an orally administered AO cocktail composed of vitamin E, N-acetylcysteine, and α-lipoic acid. AO treatment ameliorated some of the microcephaly-related aspects. Moreover, the reduced growth, lowered blood glucose levels, and the hippocampal synaptic plasticity of Mecp2-/y mice improved. However, the first-time detected intensified oxidative DNA damage in Mecp2-mutant cortex persisted. The behavioral performance, breathing regularity, and life expectancy of Mecp2-mutant mice did not improve upon AO treatment. Long-term-treated Mecp2+/- mice eventually became obese. In conclusion, the AO cocktail ameliorated a subset of symptoms of the complex RTT-related phenotype, thereby further confirming the potential merits of AO-based pharmacotherapies. Yet, it also became evident that long-term AO treatment may lose efficacy and even aggravate the metabolic disturbances in RTT. This emphasizes the importance of a constantly well-balanced redox balance for systemic well-being.

Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder.

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9-25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

Looking for "fNIRS Signature" in Autism Spectrum: A Systematic Review Starting From Preschoolers.

Accumulating evidence suggests that functional Near-Infrared Spectroscopy (fNIRS) can provide an essential bridge between our current understanding of neural circuit organization and cortical activity in the developing brain. Indeed, fNIRS allows studying brain functions through the measurement of neurovascular coupling that links neural activity to subsequent changes in cerebral blood flow and hemoglobin oxygenation levels. While the literature offers a multitude of fNIRS applications to typical development, only recently this tool has been extended to the study of neurodevelopmental disorders (NDDs). The exponential rise of scientific publications on this topic during the last years reflects the interest to identify a "fNIRS signature" as a biomarker of high translational value to support both early clinical diagnosis and treatment outcome. The purpose of this systematic review is to describe the updating clinical applications of fNIRS in NDDs, with a specific focus on preschool population. Starting from this rationale, a systematic search was conducted for relevant studies in different scientific databases (Pubmed, Scopus, and Web of Science) resulting in 13 published articles. In these studies, fNIRS was applied in individuals with Autism Spectrum Disorder (ASD) or infants at high risk of developing ASD. Both functional connectivity in resting-state conditions and task-evoked brain activation using multiple experimental paradigms were used in the selected investigations, suggesting that fNIRS might be considered a promising method for identifying early quantitative biomarkers in the autism field.