Neuroscience
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Humans exposed prenatally to ethanol can exhibit brain abnormalities and cognitive impairment similar to those seen in patients expressing mutant forms of the L1 cell adhesion molecule (L1CAM). The resemblance suggests that L1CAM may be a target for ethanol, and consistent with this idea, ethanol can inhibit L1CAM adhesion in cell lines and L1CAM-mediated outgrowth and signaling in cerebellar granule neurons. ⋯ We find that ethanol does not alter axonal polarization, L1CAM-dependent axon outgrowth or branching, or L1CAM recycling in axonal growth cones. Thus, ethanol inhibition of L1CAM is highly dependent on neuronal context.
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At the optic chiasm retinal fibers either cross the midline, or remain uncrossed. Here we trace hemispheric pathways through the marmoset chiasm and show that fibers from the lateral optic nerve pass directly toward the ipsilateral optic tract without any significant change in fiber order and without approaching the midline, while those from medial regions of the nerve decussate directly. Anterograde labeling from one eye shows that the two hemispheric pathways remain segregated through the proximal nerve and chiasm with the uncrossed confined laterally. ⋯ Recently it has been shown that this distinction is not a true dichotomy between placental mammals and marsupials, as fiber order in tree shrews and humans mirrors the marsupial pattern. Architectural differences in the mature chiasm probably reflect different developmental mechanisms regulating pathway choice. Our results therefore suggest that both the organization and development of the primate optic chiasm differ markedly from that revealed in rodents and carnivores.
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The dual-specific kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) is the mammalian orthologue of the Drosophila minibrain (MNB) protein kinase and executes diverse roles in neuronal development and adult brain physiology. DYRK1A is overexpressed in Down syndrome (DS) and has recently been implicated in several neurodegenerative diseases. In an attempt to elucidate the molecular basis of its involvement in cognitive and neurodegeneration processes, we searched for novel proteins interacting with the kinase domain of DYRK1A in the adult mouse brain and identified septin 4 (SEPT4, also known as Pnutl2/CDCrel-2). ⋯ Phosphorylation of SEPT4 by DYRK1A was inhibited by harmine, which has recently been identified as the most specific inhibitor of DYRK1A. In support of a physiological relation in the brain, we found that Dyrk1A and Sept4 are co-expressed and co-localized in neocortical neurons. These findings suggest that SEPT4 is a substrate of DYRK1A kinase and thus provide a possible link for the involvement of DYRK1A in neurodegenerative processes and in DS neuropathologies.
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Episodic ataxia type 1 (EA1) is a rare human neurological syndrome characterized by continuous myokymia and attacks of generalized ataxia that can be triggered by abrupt movements, emotional stress and fatigue. An Italian family has been identified where related members displayed continuous myokymia, episodes of ataxia, attacks characterized by myokymia only, and neuromyotonia. ⋯ In addition, heteromeric channels resulting from the co-expression of wild-type Kv1.1 and Kv1.1(F414C), or wild-type Kv1.2 and Kv1.1(F414C) subunits displayed reduced current amplitudes and altered gating properties. This indicates that the pathogenic effect of this KCNA1 mutation is likely to be related to the defective functional properties we have identified.
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Sharp wave-ripple (SPW-R) complexes are physiological pattern of network activity in the hippocampus thought to play important role in memory consolidation. During SPW-R activity the excitability of both pyramidal cells and certain types of interneurons in the CA1 region is transiently increased. As a result pyramidal cells receive inhibitory input during network oscillation, yet a relatively small group of pyramidal cells transmit their output to CA1 targets. ⋯ A fraction of CA1 pyramidal cells (25.7%), most of them distinct from the cells firing e-APs, fired orthodromic APs with highest probability before the onset of SPW-Rs. We hypothesize that putative ectopic spikes in pyramidal cells, presumably triggered by GABAergic synaptic mechanisms, by serving as output of the CA1 region might provide a reliable mechanism for optimized information transfer between hippocampus and its cortical targets during SPW-R activity. On the other hand, orthodromic APs might contribute to the initiation and synchronization of the population activity.