Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington’s Disease

Intracellular chloride (Cl–) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl– permeable GABAA receptors (GABAARs). The intracellular Cl– concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl–-importing Na+-K+-Cl– co-transporter-1 (NKCC1) and Cl– -exporting K+-Cl– co-transporter-2 (KCC2). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl–, and Cl– influx upon GABAAR activation. However, in neurons of the immature brain or in neurological disorders such as epilepsy and traumatic brain injury, impaired KCC2 function and/or enhanced NKCC1 expression lead to intracellular Cl– accumulation and GABA-mediated excitation. In Huntington’s disease (HD), KCC2- and NKCC1-mediated Cl–-regulation are also altered, which leads to GABA-mediated excitation and contributes to the development of cognitive and motor impairments. This review summarizes the role of Cl– (dys)regulation in the healthy and HD brain, with a focus on the basal ganglia (BG) circuitry and CCCs as potential therapeutic targets in the treatment of HD.

Echographic features of brain structures in children born with very low and extremely low body weight, in comparison with the clinical picture

Immature brain structures of very premature infants determine the features of the echographic picture at birth, as well as in the neoand postneonatal period. The article presents an analysis of the results of ultrasound studies of the brain (from birth to 18 months of corrected age) in comparison with the clinical and laboratory data of 489 very premature infants born with very low and extremely low body weight. The comparison of neurosonographic data and the results of clinical examination indicate that the echographic picture of the brain structures of very premature infants may differ from that of the mature infants and it does not require medical correction in the absence of neurological manifestations. The most characteristic echographic features in the first years of life are moderate dilatation of the intrathecal spaces, lateral ventricles and cisterns of the brain. Intraventricular hemorrhages in deeply premature infants occur with a high frequency, while degree III intraventricular hemorrhages, as well as periventricular and diffuse leukomalacia, are prognostically unfavorable factors leading to the development of severe neurological defects.

Encephalopathy in Preterm Infants: Advances in Neuroprotection With Caffeine

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.

Visualization of immature brain lesions: MR patterns of long-term outcomes. Case reports

The periventricular and deep white matter of the immature brain of premature infants has an increased vulnerability to various, primarily ischemic injuries. The leading mechanism of selective vulnerability of the white matter of the large hemispheres in children with a low gestation period is the lack of formation of adjacent blood circulation zones between the main arteries of the developing brain. Magnetic resonance imaging has a high sensitivity to detect damage to the brain substance, both in the acute period and in the period of long-term outcomes. Periventricular leukomalacia (PVL) is one of the variants of brain damage in premature infants and the most common term in the conclusions of diagnostic doctors (ultrasound, CT, MRI). Considering the pathomorphological criteria, not always detected changes in the white matter of the large hemispheres are PVL. Diffuse (telencephalic) gliosis and diffuse leukomalacia are ordinary and typical variants of damage to the white matter of the large hemispheres in extremely premature infants, with a gestation period of up to 30-32 weeks. In the first variant, atrophic changes predominate with a pronounced decrease in the volume of white matter and a secondary expansion of the lateral ventricles. Diffuse leukomalacia is most often mistaken for PVL, but the localization of the white matter lesion of the large hemispheres is extensive and extends beyond the peri- and paraventricular region. Clinical examples show various variants of primary non-hemorrhagic brain lesions in prematurely born children in the long-term period. The analysis of the revealed changes is carried out, taking into account current data on developing the brain and pathomorphological criteria.

Spontaneous and evoked activity patterns diverge over development

The immature brain is highly spontaneously active. Over development this activity must be integrated with emerging patterns of stimulus-evoked activity, but little is known about how this occurs. Here we investigated this question by recording spontaneous and evoked neural activity in the larval zebrafish tectum from 4 to 15 days post fertilisation. Correlations within spontaneous and evoked activity epochs were comparable over development, and their neural assemblies properties refined in similar ways. However both the similarity between evoked and spontaneous assemblies, and also the geometric distance between spontaneous and evoked patterns, decreased over development. At all stages of development evoked activity was of higher dimension than spontaneous activity. Thus spontaneous and evoked activity do not converge over development in this system, and these results do not support the hypothesis that spontaneous activity evolves to form a Bayesian prior for evoked activity.

Is Childhood General Anesthesia Exposure An Etiological Contributor to Cognitive Impairment?

General anesthesia is necessary for patients to undergo surgery and invasive procedures. However, numerous preclinical studies have demonstrated widespread developmental neurotoxicity of the commonly used anesthetics and sedatives for the immature brain. Clinical studies also suggest a strong correlation between childhood anesthesia exposure and subsequent behavioral or cognitive impairment in adulthood. These findings have attracted increasing attention of anesthesiologists, pediatricians, and caregivers about the safety of anesthesia exposure in children, especially during early childhood. Herein, the aim of this review was to present the molecular mechanism of general anesthesia and its effects on the developing brain and introduce the recent clinical evidence of changes in cognition function post-childhood general anesthesia exposure. More importantly, some of the spots will be importantly discussed to scrutinize the phenomena; only in this way, it may help minimize or eliminate relevant risk factors.

Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain

Background Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI. Methods Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60. Results We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion. Conclusion We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.