Prime pubmed learning and developmental disorders journal articles from pubmed brain anoxia

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in cullin 4B (cul4b) and cereblon (CRBN). CRBN is a substrate receptor for the cul4a/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the scffbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking cullin ubiquitin ligase activity.


Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel.Brain anoxia our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN-associated ID.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy.Brain anoxia GRIN1 encodes glun1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of glun1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria.Brain anoxia overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Maternal smoking during pregnancy is associated with developmental, cognitive, and behavioral disorders, including low birth weight, attention deficit hyperactivity disorder, learning disabilities, and drug abuse later in life. Nicotine activates the reward-driven behavior characteristic of drug abuse. Dopaminergic (DA) neurons originating from the ventral tegmental area (VTA) of the brain, which are stimulated by nicotine and other stimuli, are widely implicated in the natural reward pathway that is known to contribute to addiction.Brain anoxia in recent years, micrornas have been implicated in disrupting regulatory mechanisms due to their capability of targeting multiple genes and thus inducing downstream effects along many pathways. In order to investigate mirna expression of dopaminergic neurons from the VTA, we employed patch clamping to identify and harvest both DA and non-DA neurons from rats perinatally exposed to nicotine for use in single-cell RT-qpcr. Our data indicated that mir-140-5p and mir-140-3p were upregulated in DA neurons; while mir-140-3p and mir-212 were differentially expressed in non-DA neurons. A functional enrichment analysis was also performed on our mirna-gene prediction network and predicted that our mirnas target genes involved in drug response and neuroplasticity.Brain anoxia

Maternal immune challenge has proved to induce moderate to severe behavioral disabilities in the offspring. Cognitive/behavioral deficits are supported by changes in synaptic plasticity in different brain areas. We have reported previously that prenatal exposure to bacterial LPS could induce inhibition of hippocampal long-term potentiation (LTP) in the CA1 area of the juvenile/adult male offspring associated with spatial learning inabilities. Nevertheless, deficits in plasticity could be observed at earlier stages as shown by the early loss of long-term depression (LTD) in immature animals. Moreover, aberrant forms of plasticity were also evidenced such as the transient occurrence of LTP instead of LTD in 15-25 day-old animals.Brain anoxia this switch from LTD to LTP seemed to involve the activation of metabotropic glutamate receptor subtype 1 and 5 (mglu1/5). We have thus investigated here whether the long-term depression elicited by the direct activation of these receptors (mglu-LTD) with a selective agonist was also disturbed after prenatal stress. We find that in prenatally stressed rats, mglu1/5 stimulation elicits long-term potentiation (mglu-LTP) independently of N-methyl-D-aspartate receptors. Both mglu5 and mglu1 receptors are involved in this switch of plasticity. Moreover, this mglu-LTP is still observed at later developmental stages than previously reported, i.E. After 25 day-old. In addition, increasing synaptic GABA with tiagabine tends to inhibit mglu-LTP occurrence.Brain anoxia by contrast, long-term depression induced with the activation of CB1 cannabinoid receptor is unaffected by prenatal stress. Therefore, prenatal stress drastically alters mglu1/5-associated plasticity throughout development. MGlu-mediated plasticity is an interesting parameter to probe the long-lasting deficits reported in this model.

Through advances in both basic and clinical scientific research, pavlovian fear conditioning and extinction have become an exemplary translational model for understanding and treating anxiety disorders. Discoveries in associative and neurobiological mechanisms underlying extinction have informed techniques for optimizing exposure therapy that enhance the formation of inhibitory associations and their consolidation and retrieval over time and context.Brain anoxia strategies that enhance formation include maximizing prediction-error correction by violating expectancies, deepened extinction, occasional reinforced extinction, attentional control and removal of safety signals/behaviours. Strategies that enhance consolidation include pharmacological agonists of NMDA (i.E. D-cycloserine) and mental rehearsal. Strategies that enhance retrieval include multiple contexts, retrieval cues, and pharmacological blockade of contextual encoding. Stimulus variability and positive affect are posited to influence the formation and the retrieval of inhibitory associations. Inhibitory regulation through affect labelling is considered a complement to extinction. The translational value of extinction will be increased by more investigation of elements central to extinction itself, such as extinction generalization, and interactions with other learning processes, such as instrumental avoidance reward learning, and with other clinically relevant cognitive-emotional processes, such as self-efficacy, threat appraisal and emotion regulation, will add translational value.Brain anoxia moreover, framing fear extinction and related processes within a developmental context will increase their clinical relevance.This article is part of a discussion meeting issue ‘of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

MiR-9 is an evolutionarily conserved mirna that is abundantly expressed in area X, a basal ganglia nucleus required for vocal learning in songbirds. Here, we report that overexpression of mir-9 in area X of juvenile zebra finches impairs developmental vocal learning, resulting in a song with syllable omission, reduced similarity to the tutor song, and altered acoustic features. MiR-9 overexpression in juveniles also leads to more variable song performance in adulthood, and abolishes social context-dependent modulation of song variability.Brain anoxia we further show that these behavioral deficits are accompanied by downregulation of foxp1 and foxp2, genes known to be associated with language impairments, disruption of dopamine signaling, and widespread changes in expression of genes important in circuit development and functions. These findings demonstrate a vital role for mir-9 in basal ganglia function and vocal communication, suggesting that dysregulation of mir-9 in humans may contribute to language impairments and related neurodevelopmental disorders.