Academic literature on the topic 'Neuronal network immaturity'

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (<i>MECP2</i>) gene. Deficient K⁺-Cl^—co-transporter 2 (<i>KCC2</i>) expression is suggested to play a key role in the neurodevelopmental delay in RTT patients' neuronal networks. KCC2 is a major player in neuronal maturation by supporting the GABAergic switch, through the regulation of neuronal chlorine homeostasis. Previous studies suggest that MeCP2 mutations lead to changed <i>KCC2</i> expression levels, thereby causing a disturbance in excitation/inhibition (E/I) balance. To investigate this, we performed protein and RNA expression analysis on post mortem brain tissue from RTT patients and healthy controls. We showed that <i>KCC2</i> expression, in particular the <i>KCC2a</i> isoform, is relatively decreased in RTT patients. The expression of Na⁺-K⁺-Cl⁻ co-transporter 1 (<i>NKCC1</i>), responsible for the inward transport of chlorine, is not affected, leading to a reduced <i>KCC2</i>/<i>NKCC1</i> ratio in RTT brains. Our report confirms <i>KCC2</i> expression alterations in RTT patients in human brain tissue, which is in line with other studies, suggesting affected E/I balance could underlie neurodevelopmental defects in RTT patients.

Abstract In oligodendrocytes of the vertebrate central nervous system a complex network of transcriptional regulators is required to ensure correct and timely myelination of neuronal axons. Here we identify Zfp276, the only mammalian ZAD-domain containing zinc finger protein, as a transcriptional regulator of oligodendrocyte differentiation and central myelination downstream of Sox10. In the central nervous system, Zfp276 is exclusively expressed in mature oligodendrocytes. Oligodendroglial deletion of Zfp276 led to strongly reduced expression of myelin genes in the early postnatal mouse spinal cord. Retroviral overexpression of Zfp276 in cultured oligodendrocyte precursor cells induced precocious expression of maturation markers and myelin genes, further supporting its role in oligodendroglial differentiation. On the molecular level, Zfp276 directly binds to and represses Sox10-dependent gene regulatory regions of immaturity factors and functionally interacts with the transcriptional repressor Zeb2 to enable fast transition of oligodendrocytes to the myelinating stage.

The realization of injury to large motor neurons is embedded within contextual reference to the parallel pathways of apoptosis and necrosis of system-patterned evolution. A widespread loss of cell components occurs intracellularly and involves a reactive participation to a neuroinflammation that potentially is immunologically definable. In such terms, sporadic and hereditary forms of amyotrophic sclerosis are paralleled by the components of a reactive nature that involve the aggregation of proteins and conformational misfolding on the one hand and a powerful oxidative degradation that overwhelms the proteasome clearance mechanisms. In such terms, global participation is only one aspect of a disorder realization that induces the development of the defining systems of modulation and of injury that involves the systems of consequence as demonstrated by the overwhelming immaturity of the molecular variants of mutated superoxide dismutase. It is further to such processes of neuroinflammatory consequence that the immune system is integral to the reactive involvement of neurons as patterns of disease recognition and as the system biology of prevalent voluntarily motor character. It is highly significant to recognize various inflammatory states in the nervous system as prototype variability in phenotype expression and as incremental progression in pathogenesis. In fact a determining definition of amyotrophic lateral sclerosis is an incremental phenotype modulation within the pathways of the consequential loss and depletion of motor cell components in the first instance. Neuroinflammation proves a pattern of the contextual spread of such pathogenic progression in the realization of end-stage injury states involving neurons and neuronal networks.

IntroductionSchizophrenia is a severe debilitating condition, with elevated level of aggressiveness reaching 33% in a large sample of patients. Unaffected biological relatives of schizophrenia patients share similar though less severe neurocognitive and behavioral abnormalities seen in their affected relatives. Recent findings demonstrates that first degree relatives of schizophrenia patients are at increased risk of violence and aggressive behavior, especially during adolescence, with poor outcome. Besides, adolescents aged from 12 to 18 years old, may experience aversive and overwhelming emotions difficult to regulate due to immaturity of neuronal networks. There are evidence of an association of emotion dysregulation and violent conduct among youth. However, to our knowledge, studies among first degree relatives of psychotic patients were not performed.ObjectivesThe aim of this study was to evaluate the aggressiveness and emotion dysregulation among unaffected adolescents with fist degree family history of schizophrenia and to investigate the association linking these two entities.MethodsIn this purpose wo conducted a cross sectional descriptive study in Razi hospital during three months: from July to September 2022. Unaffected adolescents aged 12 to 18 whom first-degree relatives were diagnosed with schizophrenia according to DSM-5 criteria were included. Adolescents with psychiatric conditions or medical affections associated with psychiatric presentation were not included. Sociodemographic data were collected on a preestablished questionnaire and the following scales were used: The Life History of Aggression LHA, an 11 items self-reported tool, in the Arabic version, The Aggression Questionnaire AQ which is a 29 items self-reported scale in Arabic version and the The Emotion Regulation Questionnaire (ERQ), a 10 items self-reported measure rated on a likert scale, in the validated Arabic version. Written informed consent was obtained from the legal tutor of each adolescent.ResultsResults of this survey are ongoing.ConclusionsResults of this survey are ongoing.Disclosure of InterestNone Declared

Abstract Focal cortical dysplasia (FCD) is a highly epileptogenic cortical malformation with few treatment options. Here we generated human cortical organoids from patients with FCD type II. Using this human model, we mimicked some FCD hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. FCD cortical organoids showed downregulation of the small GTPase RHO A, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in FCD organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in FCD.

After the discovery of adult neurogenesis (stem cell-driven production of new neuronal elements), it is conceivable to find young, undifferentiated neurons mixed with mature neurons in the neural networks of the adult mammalian brain. This “canonical” neurogenesis is restricted to small stem cell niches persisting from embryonic germinal layers, yet, the genesis of new neurons has also been reported in various parenchymal brain regions. Whichever the process involved, several populations of “young” neurons can be found at different locations of the brain. Across the years, further complexity emerged: (i) molecules of immaturity can also be expressed by non-dividing cells born during embryogenesis, then maintaining immature features later on; (ii) remarkable interspecies differences exist concerning the types, location, amount of undifferentiated neurons; (iii) re-expression of immaturity can occur in aging (dematuration). These twists are introducing a somewhat different definition of neurogenesis than normally assumed, in which our knowledge of the “young” neurons is less sharp. In this emerging complexity, there is a need for complete mapping of the different “types” of young neurons, considering their role in postnatal development, plasticity, functioning, and interspecies differences. Several important aspects are at stake: the possible role(s) that the young neurons may play in maintaining brain efficiency and in prevention/repair of neurological disorders; nonetheless, the correct translation of results obtained from laboratory rodents. Hence, the open question is: how many types of undifferentiated neurons do exist in the brain, and how widespread are they?

Nearly one million premature infants die annually, due to respiratory distress. While immaturity of the lungs is a major contributor to morbidity and mortality, much less is known about the potential contribution of disturbances in central neuronal networks. Here we tested the hypothesis that central neuronal mechanisms contribute to neonatal apneas and breathing disturbances occurring within the first few hours of life. We used an animal model of prematurity, in which we administered lipopolysaccharide (LPS) into pregnant dams eliciting a maternal inflammatory response that resulted in mouse pups being born prematurely. This experimental model parallels the human condition because a large fraction of human premature births are associated with Chorioamnionitis and other forms of maternal infections. Administration of 5 micrograms of LPS to C57BL/6 mice at G17.5 resulted in delivery of pups at G18.5, about half of which were viable for at least 2 h post delivery. In a flow, whole‐body plethysmograph, premature mice from LPS‐treated dams showed abnormally large breathing patterns occurring at low frequency, which in some pups transitioned to more mature eupneic respiratory activity. Transverse, rhythmically active slices containing the pre‐Bötzinger complex, the putative respiratory rhythm generator, obtained within 30 minutes after birth from LPS pups, showed large amplitude bursts occurring at a slow and irregular frequency. Conversely term and C‐sectioned pups exhibited respiratory rhythmic activity with a smaller and more regular frequency and amplitude. Bath applied caffeine effectively stimulated and regularized burst activity. The in vitro preparations will enable us to compare the cellular mechanisms that underlie the abnormally large breathing patterns seen primarily in premature mouse pups, with the respiratory patterns generated in term and c‐sectioned pups. Understanding the central mechanisms that underlie disordered breathing in prematurity may lead to novel treatment strategies for neonatal apneas and breathing failures in human infants.Support or Funding InformationInvestigators Inter‐center seed funds

Prematurely born infants often experience frequent hypoxic episodes due to immaturity of respiratory control resulting in disturbances of cortical development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters maturation of cortical excitatory and inhibitory circuits that can be detected early with functional MRI. C57BL/6 mouse male and female pups were exposed to an intermittent hypoxia (IH) regimen from P3 to P7, corresponding to pre-term humans. Adult mice after neonatal IH exhibited motor hyperactivity and impaired motor learning in complex wheel tests. Patch clamp and evoked field potential recordings revealed increased glutamatergic synaptic transmission. To investigate the role of GABAergic inhibition on glutamatergic transmission during the developmental, we applied a selective GABAA receptor inhibitor picrotoxin. A decreased synaptic inhibitory drive in the motor cortex was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo with picrotoxin injection, and decreased interneuron density. There was also an increased tonic depolarizing effect of picrotoxin after IH on Betz cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase in regional homogeneity index after picrotoxin injection in the IH group.The increased glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH.Significance StatementThe study demonstrates that perinatal hypoxic brain injury disrupts the balance between excitatory and inhibitory neurotransmission in developing cortical networks. This disruption, potentially caused by functional deficiencies in GABAergic interneurons alongside increased glutamatergic transmission, may contribute to altered brain connectivity and the observed behavioral deficits, including hyperactivity and cognitive difficulties. This research provides insights into how perinatal brain injury disrupts the balance of neural excitation and inhibition, which can be detected as altered local resting-state fMRI connectivity. These findings contribute to our understanding of possible cellular underpinning of clinical fMRI findings after perinatal brain injury.